Nitrosated and nitrosylated α-adrenergic receptor antagonist compounds, compositions and their uses

ABSTRACT

The present invention is directed to nitrosated or nitrosylated α-adrenergic receptor antagonists, compositions comprising α-adrenergic receptor antagonists that are optionally substituted with at least one NO or NO 2  moiety and compounds that donate, transfer or release nitric oxide or elevate levels of endogenous endothelium-derived relaxing factor, and methods for treating sexual dysfunctions in males and females.

RELATED APPLICATIONS

This is a divisional of application Ser. No. 09/145,143, filed Sep. 1,1998, now U.S. Pat. No. 6,294,517, which is a continuation-in-part ofU.S. application Ser. No. 08/714,313, filed Sep. 18, 1996, issued asU.S. Pat. No. 5,994,294, which is a continuation-in-part of U.S.application Ser. No. 08/595,732, filed Feb. 2, 1996, issued as U.S. Pat.No. 5,932,538; and is a continuation-in-part of PCT/US97/01294, filedJan. 28, 1997.

FIELD OF THE INVENTION

This invention generally relates to nitrosated and/or nitrosylatedα-adrenergic receptor antagonists, compositions containing them andtheir use in treating sexual dysfunctions.

BACKGROUND OF THE INVENTION

Adequate sexual function is a complex interaction of hormonal events andpsychosocial relationships. There are four stages to sexual response asdescribed in the International Journal of Gynecology & Obstetrics,51(3):265-277 (1995). The first stage of sexual response is desire. Thesecond stage of sexual response is arousal. Both physical and emotionalstimulation may lead to breast and genital vasodilation and clitoralengorgement (vasocongestion). In the female, dilation and engorgement ofthe blood vessels in the labia and tissue surrounding the vagina producethe “orgasmic platform,” an area at the distal third of the vagina whereblood becomes sequestered. Localized perivaginal swelling and vaginallubrication make up the changes in this stage of sexual response.Subsequently, ballooning of the proximal portion of the vagina andelevation of the uterus occurs. In the male, vasodilation of thecavernosal arteries and closure of the venous channels that drain thepenis produce an erection. The third stage of sexual response is orgasm,while the fourth stage is resolution. Interruption or absence of any ofthe stages of the sexual response cycle can result in sexualdysfunction. One study found that 35% of males and 42% of femalesreported some form of sexual dysfunction. Read et al, J. Public HealthMed., 19(4):387-391 (1997).

In both pre-menopausal and menopausal females, sexual dysfunction caninclude, for example, sexual pain disorders, sexual desire disorders,sexual arousal dysfunction, orgasmic dysfunction, dyspareunia, andvaginismus. Sexual dysfunction can be caused, for example, by pregnancy,menopause, cancer, pelvic surgery, chronic medical illness ormedications.

In males, erectile dysfunction or impotence is thought to affect about10% to 15% percent of adult men. Some pharmacological methods oftreatment are available, however, such methods have not proven to behighly satisfactory or without potentially severe side-effects.Papaverine is now widely used to treat impotence. Papaverine isgenerally effective in cases where the dysfunction is psychogenic orneurogenic and where severe atherosclerosis is not involved. Injectionof papaverine, a smooth muscle relaxant, or phenoxybenzamine, anon-specific antagonist and hypotensive, into a corpus cavernosum hasbeen found to cause an erection sufficient for vaginal penetration,however, these treatments are not without the serious and often painfulside effect of priapism. Also, in cases where severe atherosclerosis isnot a cause of the dysfunction, intracavernosal injection ofphentolamine, an α-adrenergic antagonist, is used. As an alternative or,in some cases, as an adjunct to α-adrenergic blockade, prostaglandin E1(PGE1) has been administered via intracavernosal injection. A major sideeffect frequently associated with intracorprally delivered PGE1 ispenile pain and burning.

Thus, there is a need in the art for treatments of male and femalesexual dysfunctions, including treatments without the undesirable sideeffects of those agents currently used. The present invention isdirected to these, as well as other, important ends.

SUMMARY OF THE INVENTION

Nitric oxide (NO) and NO donors have been recognized as mediators ofnonvascular smooth muscle relaxation. As described herein, this effectincludes the dilation of the corpus cavernosum smooth muscle, an eventinvolved in the sexual response process for both males and females.However, the effects of NO and NO donor compounds together withα-adrenergic receptor antagonists or the modifications of α-adrenergicreceptor antagonists to be directly or indirectly linked with a nitricoxide adduct have not been investigated.

In arriving at the present invention it was recognized that the risk oftoxicities and adverse effects that are associated with high doses ofα-adrenergic receptor antagonists can be avoided by the use of suchα-adrenergic receptor antagonists when nitrosated or nitrosylated orwhen administered in conjunction with one or more compounds that donate,release or transfer nitric oxide or that elevate endogenous levels ofendothelium-derived relaxing factor (EDRF). Such toxicities and adverseeffects include postural hypotension, reflex tachycardia and otherarrhythmias, syncope and, with respect to the ergot alkaloids, nauseaand vomiting and, upon prolonged or excessive administration, vascularinsufficiency and gangrene of the extremities. The α-adrenergic receptorantagonists and compounds that donate, release or transfer nitric oxideor elevate endogenous levels of EDRF work together to permit the sameefficacy with lower doses of the α-adrenergic receptor antagonists.

Accordingly, in one aspect the invention provides novel nitrosatedand/or nitrosylated α-adrenergic receptor antagonists:NO_(n)-α-antagonists where n is 1 or 2. The α-adrenergic antagonists canbe nitrosylated or nitrosated through sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation), carbon and nitrogen.The invention also provides compositions comprising one or more of suchcompounds in a pharmaceutically acceptable carrier.

In another aspect, the invention provides compositions comprising atherapeutically effective amount of one or more α-adrenergic receptorantagonists (α-antagonist), that are optionally substituted with atleast one NO or NO₂ moiety, and one or more compounds that donate,transfer or release nitric oxide as a charged species, i.e., nitrosonium(NO⁺) or nitroxyl (NO⁻), or as the neutral species, nitric oxide (NO.),preferably in a one to ten fold molar excess, or one or more compoundsthat elevate levels of endogenous endothelium-derived relaxing factor(EDRF), preferably in a one to ten fold molar excess. The invention alsoprovides compositions comprising one or more of such compounds in apharmaceutically acceptable carrier. The α-adrenergic receptorantagonists used in the composition can be those described above andothers which are known, and can alternatively be such α-antagonistswhich have been nitrosated or nitrosylated in accordance with theinvention.

In another aspect, the invention provides methods for treating sexualdysfunctions or enhancing sexual responses in humans, including malesand females, comprising administering to an individual in need thereof atherapeutically effective amount of at least one nitrosated ornitrosylated α-antagonist.

In another aspect, the invention provides methods for treating sexualdysfunctions or enhancing sexual responses in humans, including malesand females, comprising administering to an individual in need thereofcompositions comprising a therapeutically effective amount of at leastone α-antagonist that is optionally substituted with at least one NO orNO₂ moiety, and at least one compound that donates, transfers orreleases nitric oxide as a charged species, i.e., nitrosonium (NO⁺) ornitroxyl (NO⁻), or as the neutral species, nitric oxide (NO.), and/or atleast one compound that elevates levels of endogenous EDRF. Theα-antagonist or α-antagonist directly or indirectly linked to at leastone NO or NO₂ group, and nitric oxide donor can be administeredseparately or as components of the same composition.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the percent peak erectile response in vivo compared to thatproduced by 150 μl of pap/phent/PGE1 (30 mg/ml:1 mg/ml:10 μg/ml) in theanesthetized rabbit following the intracavernosal injection of 150 μl ofyohimbine (150 μg, 500 μg), Example 1 (500 μg), and a combination ofyohimbine (150 μg) and Example 1 (500 μg). The ordinate is the percentresponse of intracavernosal pressure relative to that produced bypap/phent/PGE1 and the abscissa indicates the various drugs given.

FIG. 2 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavernosal administration of yohimbine(150 μg, 500 μg), Example 1 (500 μg), and a combination of yohimbine(150 μg) and Example 1 (500 μg). The ordinate indicates the variousdrugs given and the abscissa is the duration in minutes.

FIG. 3 shows the percent peak erectile response in vivo compared to thatproduced by 150 μl of pap/phent/PGE1 (30 mg/ml:1 mg/ml:10 μg/ml) in theanesthetized rabbit following the intracavernosal injection of 150 μl ofyohimbine (150 μg, 500 μg and 1 mg) and Example 2 (500 μg, 1 mg). Theordinate is the percent response of intracavernosal pressure relative tothat produced by pap/phent/PGE1 and the abscissa indicates the variousdoses of yohimbine and Example 2 given.

FIG. 4 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavernosal administration of yohimbine(150 μg, 500 μg and 1 mg) and Example 2 (500 μg and 1 mg). The ordinateindicates the various doses of yohimbine and Example 2 given and theabscissa is the duration in minutes.

FIG. 5A shows the effects of intracavernosal injections of Example 2(500 μg) on systemic blood pressure in the anesthetized rabbit. Forcomparison, FIG. 5B shows the effects of intracavernosal injections ofthe standard mixture of pap/phent/PGE1 on systemic blood pressure in theanesthetized rabbit.

FIG. 6 shows the percent peak erectile response in vivo compared to thatproduced by 150 μl of pap/phent/PGE1 (30 mg/ml:1 mg/ml:10 μg/ml) in theanesthetized rabbit following the intracavernosal injection ofmoxisylyte (1 mg) and Example 6 (1 mg). The ordinate is the percentresponse of intracavernosal pressure relative to that produced bypap/phent/PGE1 and the abscissa indicates the dose of moxisylyte andExample 6 given.

FIG. 7 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavernosal administration of moxisylyte (1and 2 mg) and Example 6 (1 and 2 mg). The ordinate indicates the dose ofmoxisylyte and Example 6, and the abscissa is the duration in minutes.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions may be used throughout the specification.

The term “lower alkyl” as used herein refers to branched or straightchain alkyl groups comprising one to ten carbon atoms, including, forexample, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyland the like.

The term “alkoxy” as used herein refers to R₅₀O— wherein R₅₀ is a loweralkyl group as defined above. Representative examples of alkoxy groupsinclude methoxy, ethoxy, t-butoxy and the like.

The term “alkoxyalkyl” as used herein refers to an alkoxy group aspreviously defined appended to an alkyl group as previously defined.Examples of alkoxyalkyl groups include, but are not limited to,methoxymethyl, methoxyethyl, isopropoxymethyl and the like.

The term “hydroxy” as used herein refers to —OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy group aspreviously defined appended to an alkyl group as previously defined.

The term “alkenyl” as used herein refers to a branched or straight chainC₂-C₁₀ hydrocarbon which also comprises one or more carbon-carbon doublebonds.

The term “amino” as used herein refers to —NH₂.

The term “carboxy” as used herein refers to —C(O)O—.

The term “nitrate” as used herein refers to —O—NO₂.

The term “amido” as used herein refers to —C(O)NH—.

The term “alkylamino” as used herein refers to R₁₁NH— wherein R₁₁ is alower alkyl group. Alkylamino groups include, for example, methylamino,ethylamino, butylamino, and the like.

The term “alkylamido” as used herein refers to —C(O)NR₁₁— wherein R₁₁ isas defined above.

The term “dialkylamino” as used herein refers to R₁₂R₁₃N— wherein R₁₂and R₁₃ are independently a lower alkyl group as defined above.Dialkylamino groups include, for example, dimethylamino, diethylamino,methyl propylamino and the like.

The term “nitro” as used herein refers to the group —NO₂ and“nitrosated” refers to compounds that have been substituted therewith.

The term “nitroso” as used herein refers to the group —NO and“nitrosylated” refers to compounds that have been substituted therewith.

The term “aryl” as used herein refers to a mono- or bi-cycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl,and the like. Aryl groups (including bicyclic aryl groups) can beunsubstituted or substituted with one, two or three substituentsindependently selected from lower alkyl, haloalkyl, alkoxy, amino,alkylamino, dialkylamino, hydroxy, halo, and nitro. In addition,substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term “arylalkyl” as used herein refers to a lower alkyl radical towhich is appended an aryl group. Representative arylalkyl groupsinclude, for example, benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl and the like.

The term “cycloalkyl” as used herein refers to an alicyclic groupcomprising from about 3 to about 7 carbon atoms including, but notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike.

The term “halogen” or “halo” as used herein refers to I, Br, Cl, or F.The term “haloalkyl” as used herein refers to a lower alkyl radical, asdefined above, bearing at least one halogen substituent. Haloalkylgroups include, for example, chloromethyl, fluoroethyl, trifluoromethyland the like.

The term “heteroaryl” as used herein refers to a mono- or bi-cyclic ringsystem containing one or two aromatic rings and containing at least onenitrogen, oxygen, or sulfur atom in an aromatic ring. Heteroaryl groups(including bicyclic heteroaryl groups) can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino,hydroxy, halo and nitro. Heteroaryl groups include, for example,pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole,thiazole, isothiazole, benzothiazole, benzoxazole, thiadiazole, oxazole,pyrrole, imidazole, isoxazole and the like.

The term “heterocyclic ring” refers to any 3-, 4-, 5-, 6-, or 7-memberednonaromatic ring containing at least one nitrogen atom, oxygen atom, orsulfur atom which is bonded to an atom which is not part of theheterocyclic ring.

The term “arylheterocyclic ring” as used herein refers to a bi- ortri-cyclic ring comprised of an aryl ring as previously defined appendedvia two adjacent carbon atoms of the aryl group to a heterocyclic ringas previously defined.

The term “heterocyclic compounds” as used herein refers to mono- andpolycyclic compounds containing at least one heteroaryl or heterocyclicring.

The term “bridged cycloalkyl” as used herein refers to two or morecycloalkyl radicals fused via adjacent or non-adjacent carbon atoms,including, for example, adamantyl and decahydronapthyl.

The term “carbonyl” as used herein refers to —C(O)—.

The term “carboxylic acid” as used herein refers to —C(O)OH.

The term “carboxylic ester” as used herein refers to —C(O)OR₅₀, whereinR₅₀ is a lower alkyl group as defined herein.

The term “phosphoryl” as used herein refers to —P(R₇₀)(R₇₁), wherein R₇₀is a lone pair of electrons, sulfur or oxygen and R₇₁ is independently ahydrogen, a lower alkyl, an alkoxy, an alkylamino, a hydroxy or an aryl.

The term “sexual dysfunction” generally includes any sexual dysfunctionin an animal, preferably a mammal, more preferably a human. The animalcan be male or female. Sexual dysfunction may include, for example,sexual desire disorders, sexual arousal disorders, orgasmic disordersand sexual pain disorders. Female sexual dysfunction refers to anyfemale sexual dysfunction including, for example, sexual desiredysfunction, sexual arousal dysfunction, orgasmic dysfunction, sexualpain disorders, dyspareunia, and vaginismus. The female may bepre-menopausal or menopausal. Male sexual dysfunction refers to any malesexual dysfunction including, for example, male erectile dysfunction andimpotence.

While there are obvious differences in the sexual response between malesand females, one common aspect of the sexual response is the erectileresponse. As described in U.S. Pat. No. 5,565,466, the disclosure ofwhich is incorporated herein by reference in its entirety, the erectileresponse in both males and females is the result of engorgement of theerectile tissues of the genitalia with blood caused by the relaxation ofsmooth muscles in the arteries serving the genitalia.

The vasculature which serves erectile tissue in males and females issimilar. In particular, the arterial circulation of the erectile tissuesof the genitalia derives from the common iliac artery which branchesfrom the abdominal aorta. The common iliac artery bifurcates into theinternal and external iliac arteries. The internal pudic artery arisesfrom the smaller of two terminal branches of the anterior trunk of theinternal iliac artery. In the female, the internal pudic artery branchesinto the superficial perineal artery which supplies the labia pudenda.The internal pudic artery also branches into the artery of the bulbwhich supplies the bulbi vestibuli and the erectile tissue of thevagina. The artery of the corpus cavernosum, another branch of theinternal pudic artery supplies the cavernous body of the clitoris. Stillanother branch of the internal pudic artery is the arteria dorsalisclitoridis which supplies the dorsum of the clitoris and terminates inthe glans and membranous folds surrounding the clitoris which correspondto the prepuce of the male.

In the male, the internal pudic artery branches into the dorsal arteryof the penis (which itself branches into a left and right branch) andthe artery of the corpus cavemosum, all of which supply blood to thecorpus cavernosum. The dorsal artery of the penis is analogous to theartery dorsalis clitoridis in the female, while the artery of the corpuscavemosum in the male is analogous to the artery of the same name in thefemale.

The male erectile response is regulated by the autonomic nervous systemwhich controls blood flow to the penis via the interaction of peripheralnerves associated with the arterial vessels in and around the corpuscavemosum. In the non-aroused or non-erect state, the arteries servingthe corpus cavernosum are maintained in a relatively constricted state,thereby limiting the blood flow to the corpus cavemosum. In the arousedstate, the smooth muscles associated with the arteries relax and bloodflow to the corpus cavernosum greatly increases, causing expansion andrigidity of the penis. Smooth muscle contraction opens valves throughwhich blood can flow from the corpus cavemosum into the extracavernosalveins. When the relevant smooth muscles relax, the valves closediminishing venous outflow from the corpus cavemosum. When accompaniedby increased arterial blood flow into the corpus cavemosum, this resultsin engorgement of the corpus cavemosum and an erection.

The pre-orgasmic sexual response in females can be broken down intodistinct phases. Both the excitement phase and the plateau phase involvevasodilation and engorgement (vasocongestion) of the genitalia witharterial blood in a manner analogous to the male erectile response.

The excitement phase of the female sexual response is characterized byvasocongestion in the walls of the vagina which leads to thetransudation of vaginal fluids and vaginal lubrication. Further, theinner one-third of the vaginal barrel expands and the cervix and thebody of the uterus become elevated. This is accompanied by theflattening and elevation of the labia majora and an increase in clitoralsize.

The plateau phase follows the excitement phase in the female sexualresponse and is characterized by prominent vasocongestion in the outerone-third of the vagina, causing a narrowing of the opening of thevagina and a retraction of the shaft and the glans of the clitorisagainst the symphysis pubis. These responses are also accompanied by amarked vasocongestion of the labia.

The vasocongestive aspects of the female sexual response are notrestricted to the genitalia in that areolar engorgement also occurs,sometimes to the extent that it masks the antecedent nipple erectionthat usually accompanies the excitement phase.

The vasodilation and vasocongestive responses described herein may alsobe induced by pharmacological action without psychological stimulationor arousal by the female. Similarly, the male sexual response may alsobe induced by pharmacological action without psychological stimulationor arousal.

The present invention is directed to the treatment and/or prevention ofsexual dysfunctions in animals, including males and females, byadministering the compounds and compositions described herein. Thepresent invention is also directed to improving and/or enhancing thesexual response in animals, including males and females, byadministering the compounds and/or compositions described herein. Thenovel compounds and novel compositions of the present invention aredescribed in more detail below.

The α-adrenergic receptor antagonists that are nitrosated ornitrosylated in accordance with the invention and/or are included in thecompositions of the invention can be any of those known in the art,including those exemplified below. Structurally, the α-antagonists cangenerally be categorized as haloalkylamines, imidazolines, quinozolines,indole derivatives, phenoxypropanolamines, alcohols, alkaloids, amines,piperizines and piperidines.

The first group of α-antagonists are the haloalkylamines thatirreversibly block α₁- and α₂-adrenergic receptors. Included in thisgroup are, for example, phenoxybenzamine and dibenamine.Phenoxybenzamine is used in the treatment of pheochromocytomas, tumorsof the adrenal medulla and sympathetic neurons that secretecatecholamines into the circulation. It controls episodes of severehypertension and minimizes other adverse effects of catecholamines suchas contraction of plasma volume and injury of the myocardium.

Another group of α-antagonists are the imidazolines. These includephentolamine and tolazoline. Phentolamine has similar affinity for α₁and α₂ receptors. Phentolamine is used in short-term control ofhypertension in patients with pheochromocytoma and direct,intracavernous injection of phentolamine (usually in combination withpapaverine) has been proposed as a treatment for male sexualdysfunction. Tolazoline is used in the treatment of persistent pulmonaryhypertension in neonates. Other imidazolines include, for example,idazoxan, deriglidole, RX 821002, BRL 44408 and BRL 44409 (see, Young etal, Eur. J. Pharm., 168:381-386 (1989), the disclosure of which isincorporated herein by reference).

Another group of α-antagonist compounds that are contemplated are thequinazolines. These include, for example, prazosine, a very potent andselective a,adrenergic antagonist, terazosin, doxazosin, alfuzosin,bunazosin, ketanserin, trimazosin and abanoquil. This group of compoundsis principally used in the treatment of primary systemic hypertensionand also in the treatment of congestive heart failure.

Another class of α-adrenergic blocking agents are indoles and indolederivatives. These include, for example, carvedilol and BAM 1303.

Another class of α-adrenergic blocking agents are alcohols. Theseinclude, for example, labetelol and ifenprodil.

Another class of α-adrenergic blocking agents are alkaloids. Theseinclude, for example, “ergotoxine” which is a mixture of threealkaloids: ergocornine, ergocristine and ergocryptine. Both natural anddihydrogenated peptide alkaloids produce α-adrenergic blockade. Theprincipal uses are to stimulate contraction of the uterus post-partumand to relieve the pain of migraine headaches. Another indole alkaloidis yohimbine. This compound is a competitive antagonist that isselective for α₂-adrenergic receptors. In humans, it has been observedto increase blood pressure and heart rate and has been used in thetreatment of male sexual dysfunction. Other alkaloid α-blockers includerauwolscine, corynathine, raubascine, tetrahydroalstonine, apoyohimbine,akuammigine, β-yohimbine, yohimbol, pseudoyohimbine andepi-3α-yohimbine.

Another class of α-adrenergic blocking agents are amines. These include,for example, tamsulosin, benoxathian, atipamezole, BE 2254, WB 4101 andHU-723.

Another class of α-adrenergic blocking agents are piperizines, whichinclude, for example, naftopil and saterinone.

Another class of α-adrenergic blocking agents are piperidines. Theseinclude, for example, haloperidol.

Each of the above contemplated α-antagonists is described more fully inthe literature, such as in Goodman and Gilman, The Pharmacological Basisof Therapeutics (8th Edition), McGraw-Hill (1993), the disclosure ofwhich is incorporated by reference herein in its entirety.

One skilled in the art will understand that the compounds of the presentinvention which have one or more asymmetric carbon atoms may exist asthe optically pure enantiomers, pure diastereomers, mixtures ofenantiomers, mixtures of diastereomers, racemic mixtures of enantiomers,diastereomeric racemates or mixtures of diastereomeric racemates. It isintended that the present invention anticipates and includes within itsscope all such isomers and mixtures thereof.

One embodiment of the invention includes substituted compounds of theformula I:

wherein R_(a) is a hydrogen or an alkoxy;

R_(b) is:

wherein a is an integer of 2 or 3;

R_(c) is a heteroaryl, a heterocyclic ring, a lower alkyl, ahydroxyalkyl, or an arylheterocyclic ring;

D is (i) —NO, (ii) —NO₂, (iii)—C(R_(d))—O—C(O)—Y—Z—(C(R_(e))(R_(f)))_(p)—T—Q, wherein R_(d) is ahydrogen, a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or aheteroaryl; Y is oxygen, sulfur, carbon or NR_(i) wherein R_(i) is ahydrogen or a lower alkyl; R_(e) and R_(f) are each independently ahydrogen, a lower alkyl, a haloalkyl, a cycloalkyl, an alkoxy, an aryl,a heteroaryl, an arylalkyl, an amino, an alkylamino, a dialkylamino, anamido, an alkylamido, a carboxylic acid, a carboxylic ester, acarboxamido, a carboxy or —T—Q, or R_(e) and R_(f) taken together are acarbonyl, a heterocyclic ring, a cycloalkyl or a bridged cycloalkyl; pis an integer from 1 to 10; T is independently a covalent bond, oxygen,sulfur or nitrogen; Z is a covalent bond, a lower alkyl, a haloalkyl, acycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroalkyl, anarylheterocyclic ring or (C(R_(e))(R_(f)))_(p), and Q is —NO or —NO₂;(iv) —C(O)—Y—Z—(G—(C(R_(e)(R_(f)))_(q)—T—Q)_(p) wherein G is a covalentbond, —T—C(O)—, —C(O)—T— or T, wherein q is an integer from 0 or 5, andwherein R_(e), R_(f), p, Q, Z, Y and T are as defined above, or (v)—P—Z—(G—(C(R_(e))(R_(f)))_(q)—T—Q)_(p), wherein P is a carbonyl, aphosphoryl or a silyl, and wherein R_(e), R_(f), p, q, Q, T, Z and G areas defined above.

Another embodiment of the invention includes substituted compounds ofthe formula II:

wherein R_(g) is:

wherein D_(l) is a hydrogen or D, wherein D is as defined above, withthe proviso that D_(l) must be D if there is no other D in the molecule.

Another embodiment of the invention includes substituted compounds ofthe formula III:

wherein R_(h) is a hydrogen, —C(O)—OR_(d) or —C(O)—X; wherein X is(1)—Y—(C(R_(e)(R_(f))_(p)—G—(C(R_(e)(R_(f))_(p)—T—Q; wherein G is acovalent bond, —T—C(O)—, —C(O)—T—, or —C(Y—C(O)—R_(m))—, wherein R_(m)is a heteroaryl or a heterocyclic ring; and wherein Y, R_(d), R_(e),R_(f), p, Q and T are as defined above; or

wherein W is a heterocyclic ring or NR_(i)R′_(i) wherein R_(i) andR′_(i) are independently a lower alkyl, an aryl or an alkenyl; andwherein R_(j) is hydrogen, —D or —(O)CR_(d) wherein D and R_(d) are asdefined above.

Another embodiment of the invention includes substituted compounds ofthe formula IV:

wherein A₁ is oxygen or methylene, and X and R_(j) are as defined above.

Another embodiment of the invention includes substituted compounds ofthe formula V:

wherein R_(k) is a hydrogen or a lower alkyl; and

wherein R_(l) is:

wherein b is an integer of 0 or 1; D and D₁ are as defined above; andR_(n) is:

wherein A₂ is oxygen or sulfur.

Another embodiment of the invention includes substituted compounds ofthe formula VI:

wherein R_(o) is:

and R_(p) is:

and R_(k), D_(l) and D are as defined above.

Another embodiment of the invention includes substituted compounds ofthe formula VII:

wherein R_(d), T and D are defined as above.

Another embodiment of the invention includes substituted compounds ofthe formula VIII:

wherein a, R_(i), R′_(i), R_(e), R_(f) and D are as defined above.

The present invention also relates to processes for preparing thecompounds of formula (I), (II), (III), (IV), (V), (VI), (VII) and (VIII)and to the intermediates useful in such processes.

Some of the nitrosated and nitrosylated α-antagonists of the presentinvention may be synthesized as shown in reaction Schemes I through XXIpresented below, wherein R_(a), R_(b), R_(c), R_(d), R_(e), R_(f),R_(g), R_(h), R_(i), R′_(i), R_(j), R_(k), R_(l), R_(m), R_(n), R_(o),R_(p), A₁, A₂, a, n, W and X are as defined above or as depicted in thereaction schemes for formulas I, II, III, IV, V, VI, VII or VIII. P¹ isan oxygen protecting group and P² is a sulfur protecting group. Thereactions are performed in solvents appropriate to the reagents andmaterials used are suitable for the transformations being effected. Itis understood by one skilled in the art of organic synthesis that thefunctionality present in the molecule must be consistent with thechemical transformation proposed. This will, on occasion, necessitatejudgment by the routineer as to the order of synthetic steps, protectinggroups required, and deprotection conditions. Substituents on thestarting materials may be incompatible with some of the reactionconditions required in some of the methods described, but alternativemethods and substituents compatible with the reaction conditions will bereadily apparent to one skilled in the art. The use of sulfur and oxygenprotecting groups is well known in the art for protecting thiol andalcohol groups against undesirable reactions during a syntheticprocedure and many such protecting groups are known, such as thosedescribed by T. H. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York (1991), the disclosure ofwhich is incorporated by reference herein in its entirety.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by oneskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Nitroso compounds of formula (I) wherein R_(a), R_(b), R_(e), R_(f), andp are as defined above and an O-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme I. Theamine group of the quinazoline of the formula 1 is converted to theamide of the formula 2 wherein p, R_(e) and R_(f) are as defined aboveby reaction with an appropriate protected alcohol containing activatedacylating agent wherein P¹ is as defined above. Preferred methods forthe formation of amides are reacting the amine with the preformed acidchloride or symmetrical anhydride of the protected alcohol-containingacid. Preferred protecting groups for the alcohol moiety are silylethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.Deprotection of the hydroxyl moiety (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactionwith a suitable nitrosylating agent such as thionyl chloride nitrite,thionyl dinitrite, or nitrosium tetrafluoroborate in a suitableanhydrous solvent such as dichloromethane, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of the formula IA.

Nitroso compounds of formula (I) wherein R_(a), R_(b), R_(e), R_(f), andp are as defined above and an S-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme II. Theamine group of the quinazoline of the formula 1 is converted to theamide of the formula 3, wherein p, R_(e) and R_(f) are defined as aboveby reaction with an appropriate protected thiol-containing activatedacylating agent wherein P² is as defined above. Preferred methods forthe formation of amides are reacting the amine with the preformed acidchloride or symmetrical anhydride of the protected thiol containingacid. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether ora S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while an aqueousbase is typically utilized to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula IB.Alternatively, treatment of compound 3 with a stoichiometric quantity ofsodium nitrite in aqueous acid affords the compound of the formula IB.

Nitro compounds of formula (I) wherein R_(a), R_(b), R_(e) R_(f), and pare defined as above and an O-nitrosated amide is representative of theD group as defined above may be prepared according to Scheme III. Theamine group of the quinazoline of the formula 1 is converted to theamide of the formula IC wherein p, R_(e) and R_(f) are defined as aboveby reaction with an appropriate nitrate containing activated acylatingagent. Preferred methods for the formation of amides are reacting theamine with the preformed acid chloride or symmetrical anhydride of thenitrate containing acid to afford the compound of the formula IC.

Nitroso compounds of formula (II) wherein R_(e) R_(f), R_(g), and p areas defined above and an O-nitrosylated acyl imidazoline isrepresentative of the D group as defined above may be prepared accordingto Scheme IV. The imidazoline group of the formula 4 is converted to theacyl imidazoline of the formula 5 wherein p, R_(e) and R_(f) are definedas above by reaction with an appropriate protected alcohol containingactivated acylating agent wherein P¹ is as defined above. Preferredmethods for the formation of acyl imidazolines are reacting theimidazoline with the preformed acid chloride or symmetrical anhydride ofthe protected alcohol containing acid. Preferred protecting groups forthe alcohol moiety are silyl ethers such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIIA.

Nitroso compounds of formula (II) wherein R_(e) R_(f), R_(g), and p aredefined as above and an S-nitrosylated acyl imidazoline isrepresentative of the D group as defined above may be prepared accordingto Scheme V. The imidazoline group of the formula 4 is converted to theacyl imidazoline of the formula 6 wherein p, R_(e) and R_(f) are definedas above by reaction with an appropriate protected alcohol containingactivated acylating agent wherein P² is as defined above. Preferredmethods for the formation of acyl imidazolines are reacting theimidazoline with the preformed acid chloride or symmetrical anhydride ofthe protected thiol containing acid. Preferred protecting groups for thethiol moiety are as a thioester such as a thioacetate or thiobenzoate,as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically used tohydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF or acetonitrile with or without an amine base such aspyridine or triethylamine affords the compound of the formula IIB.Alternatively, treatment of compound 6 with a stoichiometric quantity ofsodium nitrite in aqueous acid affords the compound of the formula IIB.

Nitro compounds of formula (II) wherein R_(e), R_(f), R_(g), and p aredefined as above and an O-nitrosated acyl imidazoline is representativeof the D group as defined above may be prepared according to Scheme VI.The imidazoline group of the formula 4 is converted to the acylimidazoline of the formula IIC wherein p, R_(e) and R_(f) are defined asabove by reaction with an appropriate nitrate containing activatedacylating agent. Preferred methods for the formation of acylimidazolines are reacting the amine with the preformed acid chloride orsymmetrical anhydride of the nitrate containing acid to afford thecompound of the formula IC.

Nitroso compounds of formula (III) wherein R_(e), R_(f), R_(h), R_(j),and p are defined as above and an O-nitrosylated ester is representativeof the D group as defined above may be prepared according to Scheme VII.The alcohol group of formula 7 is converted to the ester of formula 8wherein p, R_(e) and R_(f) are defined as above by reaction with anappropriate protected alcohol containing activated acylating agentwherein P¹ is as defined above. Preferred methods for the formation ofesters are reacting the alcohol with the preformed acid chloride orsymmetrical anhydride of the protected alcohol containing acid.Preferred protecting groups for the alcohol moiety are silyl ethers suchas a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection ofthe hydroxyl moiety (fluoride ion is the preferred method for removingsilyl ether protecting groups) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,or nitrosium tetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIIIA.

Nitroso compounds of formula (III) wherein R_(e), R_(f), R_(h), R_(j),and p are defined as above and an S-nitrosylated ester is representativeof the D group as defined above may be prepared according to SchemeVIII. The alcohol group of the formula 7 is converted to the ester ofthe formula 9 wherein p, R_(e) and R_(f) are defined as above byreaction with an appropriate protected thiol containing activatedacylating agent wherein P² is as defined above. Preferred methods forthe formation of esters are reacting the alcohol with the preformed acidchloride or symmetrical anhydride of the protected thiol containingacid. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether ora S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while an aqueousbase is typically used to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula IIIB.Alternatively, treatment of compound 9 with a stoichiometric quantity ofsodium nitrite in aqueous acid affords the compound of the formula IIIB.

Nitro compounds of formula (III) wherein R_(e), R_(f), R_(h), R_(j), andp are defined as above and an O-nitrosated ester is representative ofthe D group as defined above may be prepared according to Scheme IX. Thealcohol group of the formula 7 is converted to the ester of the formulaIIIC wherein p, R_(e) and R_(f) are defined as above by reaction with anappropriate nitrate containing activated acylating agent. Preferredmethods for the formation of esters are reacting the alcohol with thepreformed acid chloride or symmetrical anhydride of the nitratecontaining acid to afford a compound of the formula IIIC.

Nitroso compounds of formula (IV) wherein A₁, R_(e), R_(f), R_(h),R_(j), and p are defined as above and an O-nitrosylated ester isrepresentative of the X group as defined above may be prepared accordingto Scheme X. An acid of the formula 10 is converted into the ester ofthe formula 11 wherein p, R_(e), and R_(f) are defined as above byreaction with an appropriate monoprotected diol. Preferred methods forthe preparation of esters are initially forming the mixed anhydride viareaction of 10 with a chloroformate such as isobutylchloroformate in thepresence of a non nucleophilic base such as triethylamine in ananhydrous inert solvent such as dichloromethane, diethylether, or THF.The mixed anhydride is then reacted with the monoprotected alcoholpreferably in the presence of a condensation catalyst such as4-dimethylamino pyridine. Alternatively, the acid 10 may be firstconverted to the acid chloride by treatment with oxalyl chloride in thepresence of a catalytic amount of DMF. The acid chloride is then reactedwith the monoprotected alcohol preferably in the presence of acondensation catalyst such as 4-dimethylaminopyridine and a tertiaryamine base such as triethyl amine to afford the ester 11. Alternatively,the acid 10 and monoprotected diol may be coupled to afford 11 bytreatment with a dehydration agent such as dicyclohexylcarbodiimide.Preferred protecting groups for the alcohol moiety are silyl ethers suchas a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection ofthe hydroxyl moiety (fluoride ion is the preferred method for removingsilyl ether protecting groups) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,or nitrosium tetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile affords the compound of theformula IVA.

Nitroso compounds of formula (IV) wherein A₁, R_(e), R_(f), R_(h), R_(j)and p are defined as above and an S-nitrosylated ester is representativeof the X group as defined above may be prepared according to Scheme XI.An acid of the formula 10 is converted into the ester of the formula 12wherein p, R_(e), and R_(f) are defined as above and a S-nitrosylatedester is representative of the X group as defined above by reaction withan appropriate protected thiol containing alcohol. Preferred methods forthe preparation of esters are initially forming the mixed anhydride viareaction of with a chloroformate such as isobutylchloroformate in thepresence of a non nucleophilic base such as triethylamine in ananhydrous inert solvent such as diethylether or THF. The mixed anhydrideis then reacted with the thiol containing alcohol preferably in thepresence of a condensation catalyst such as 4-dimethylaminopyridine.Alternatively, the acid 10 may be first converted to the acid chloridebe treatment with oxalyl chloride in the presence of a catalytic amountof DMF. The acid chloride is then reacted with the monoprotected thiolpreferably in the presence of a condensation catalyst such as4-dimethylaminopyridine and a tertiary amine base such as triethyl amineto afford the ester 12. Alternatively, the acid and thiol containingalcohol may be coupled to afford 12 by treatment with a dehydrationagent such as dicyclohexylcarbodiimide. Preferred protecting groups forthe thiol moiety are as a thioester such as a thioacetate orthiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether, or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute. aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically used tohydrolyze thiolesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF or acetonitrile with or without an amine base such aspyridine or triethylamine affords the compound of the formula IVB.Alternatively, treatment of compound 12 with a stoichiometric quantityof sodium nitrite in aqueous acid affords the compound of the formulaIVB.

Nitro compounds of formula (IV) wherein A₁, R_(e), R_(f), R_(h), R_(j)and p are defined as above and an O-nitrosated ester is representativeof the X group as defined above may be prepared according to Scheme XII.An acid of the formula 10 is converted into the ester of the formula IVCwherein p, R_(e),and R_(f) are defined as above by reaction with anappropriate nitrate containing alcohol. Preferred methods for thepreparation of esters are initially forming the mixed anhydride viareaction of 10 with a chloroformate such as isobutylchloroformate in thepresence of a non nucleophilic base such as triethylamine in ananhydrous inert solvent such as dichloromethane, diethylether, or THF.The mixed anhydride is then reacted with the nitrate containing alcoholpreferably in the presence of a condensation catalyst such as4-dimethylamino-pyridine. Alternatively, the acid 10 may be firstconverted to the acid chloride by treatment with oxalyl chloride in thepresence of a catalytic amount of DMF. The acid chloride is then reactedwith the nitrate containing alcohol preferably in the presence of acondensation catalyst such as 4-dimethylaminopyridine and a tertiaryamine base such as triethyl amine to afford the a compound of theformula IVC. Alternatively, the acid 10 and nitrate containing alcoholmay be coupled to afford a compound of the formula IVC by treatment witha dehydration agent such as dicyclohexylcarbodiimide.

Nitroso compounds of formula (V) wherein R_(e), R_(f), R_(k), R_(l),R_(n), and p are defined as above and an O-nitrosylated N-acyloxyalkylamine is representative of the D group as defined above may be preparedaccording to Scheme XIII. The amine group of the compound of the formula13 is converted to the N-acyloxyalkyl amine of the formula 14 wherein p,R_(e), and R_(f), are defined as above by reaction with an appropriateprotected alcohol containing chloromethyl acyl derivative wherein P¹ isas defined above. Preferred methods for the formation of N-acyloxyalkylamines are reacting the amine with the preformed chloromethylacyloxyalkyl derivative of the protected alcohol. Preferred protectinggroups for the alcohol moiety are silyl ethers such as a triethylsilylor a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaVA.

Nitroso compounds of formula (V) wherein R_(e), R_(f), R_(k), R_(l),R_(n), and p are defined as above and an S-nitrosylated N-acyloxyalkylamine is representative of the D group as defined above may be preparedaccording to Scheme XIV. The amine group of the compound of the formula13 is converted to the N-acyloxyalkyl amine of the formula 15 wherein p,R_(e) and R_(f), are defined as above by reaction with an appropriateprotected thiol containing chloromethyl acyl derivative wherein P² is asdefined above. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a tetrahydropyranyl thioether. Deprotection of the thiol moiety(triphenylphosphine in water and sodium borohydride are preferredmethods for reducing disulfide groups while an aqueous base is typicallyused to hydrolyze thioesters and N-methoxymethyl thiocarbamates andmercuric trifluoroacetate or silver nitrate are used to remove atetrahydropyranyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula VB.

Nitro compounds of formula (V) wherein R_(e), R_(f), R_(k), R_(l),R_(n), and p are defined as above and an O-nitrosated N-acyloxyalkylamine is representative of the D group as defined above may be preparedaccording to Scheme XV. The amine group of the compound of the formula13 is converted to the N-acyloxyalkyl amine of the formula VC wherein p,R_(e) and R_(f) are defined as above by reaction with an appropriatenitrate containing chloromethyl acyl derivative. Preferred methods forthe formation of N-acyloxyalkyl amines are reacting the amine with thepreformed chloromethyl acyloxyalkyl derivative of the nitrate containingderivative to afford the compound of the formula VC.

Nitroso compounds of formula (VII) wherein R_(d), R_(e), R_(f), T, and pare defined as above and an O-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme XVI.The amine group of the dihydropyridine of the formula 14 is converted tothe amide of the formula 15 wherein p, R_(e) and R_(f) are defined asabove by reaction with an appropriate protected alcohol containingactivated acylating agent wherein P¹ is as defined above. Preferredmethods for the formation of amides are reacting the amine with thepreformed acid chloride or symmetrical anhydride of the protectedalcohol containing acid. Preferred protecting groups for the alcoholmoiety are silyl ethers such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaVIIA.

Nitroso compounds of formula (VII) wherein R_(d), R_(e), R_(f), T, and pare defined as above and an S-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme XVII.The amine group of the dihydropyridine of the formula 14 is converted tothe amide of the formula 16 wherein p, R_(e), and R_(f) are defined asabove by reaction with an appropriate protected thiol containingactivated acylating agent wherein P² is defined above. Preferred methodsfor the formation of amides are reacting the amine with the preformedacid chloride or symmetrical anhydride of the protected thiol containingacid. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether ora S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically used to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula VIIB.Alternatively, treatment of compound 16 with a stoichiometric quantityof sodium nitrite in aqueous acid affords the compound of the formulaVIIB.

Nitro compounds of formula (VII) wherein R_(d), R_(e), R_(f), T, and pare defined as above and an O-nitrosated amide is representative of theD group as defined above may be prepared according to Scheme XVIII. Theamine group of the dihydropyridine of the formula 14 is converted to theamide of the formula VIIC wherein p, R_(e) and R_(f) are defined asabove by reaction with an appropriate nitrate containing activatedacylating agent. Preferred methods for the formation of amides arereacting the amine with the preformed acid chloride or symmetricalanhydride of the nitrate containing acid to afford the compound of theformula VIIC.

Nitroso compounds of formula (VIII) wherein R_(e), R_(f), a and p are asdefined as above and an O-nitrosylated ester is representative of the Dgroup as defined above may be prepared according to Scheme XIX. Thehydroxyl group of the phenol of the formula 15 is converted to the esterof the formula 16 wherein a, p, R_(e) and R_(f) are defined as above byreaction with an appropriate protected alcohol containing activatedacylating agent wherein P¹ is as defined above. Preferred methods forthe formation of esters are reacting the hydroxyl with the preformedacid chloride or symmetrical anhydride of the protected alcoholcontaining acid. Preferred protecting groups for the alcohol moiety aresilyl ethers such as a trimethylsilyl or a tert-butyldimethylsilylether. Deprotection of the hydroxyl moiety (fluoride ion is thepreferred method for removing silyl ether protecting groups) followed byreaction with a suitable nitrosylating agent such as thionyl chloridenitrite, thionyl dinitrite, or nitrosium tetrafluoroborate in a suitableanhydrous solvent such as dichloromethane, THF, DMF or acetonitrile withor without an amine base such as pyridine or triethylamine affords thecompound of the formula VIIIA.

Nitroso compounds of formula (VIII) wherein R_(e), R_(f), R_(i), R′_(i),a and p are as defined above and an S-nitrosylated ester isrepresentative of the D group as defined above may be prepared accordingto Scheme XX. The hydroxyl group of the phenol of the formula 17 isconverted to the ester of the formula 19 wherein a, p, R_(e) and R_(f)are defined as above by reaction with an appropriate protected thiolcontaining activated acylating agent wherein P² is as defined above.Preferred methods for the formation of esters are reacting the hydroxylwith the preformed acid chloride or symmetrical anhydride of theprotected thiol containing acid. Preferred protecting groups for thethiol moiety are as a thioester such as a thioacetate or thiobenzoate,as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenyl-phosphine in water and sodium borohydride are preferredmethods for reducing disulfide groups while aqueous base is typicallyused to hydrolyze thioesters and N-methoxymethyl thiocarbamates andmercuric trifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF or acetonitrile with or without an amine base such aspyridine or triethylamine affords the compound of the formula VIIIB.Alternatively, treatment of compound 17 with a stoichiometric quantityof sodium nitrite in aqueous acid affords the compound of the formulaVIIIB.

Nitro compounds of formula (VIII) wherein R_(e), R_(f), R_(i) , R′_(i),a and p are as defined above an O-nitrosated ester is representative ofthe D group as defined above may be prepared according to Scheme XXI.The hydroxyl group of the phenol of the formula 15 is converted to theester of the formula VIIIC wherein a, p, R_(e) and R_(f) are as definedabove by reaction with an appropriate nitrate containing activatedacylating agent. Preferred methods for the formation of amides arereacting the amine with the preformed acid chloride or symmetricalanhydride of the nitrate containing acid to afford the compound of theformula VIIIC.

As discussed above, another aspect of the invention provides acomposition comprising a therapeutically effective amount of anα-adrenergic receptor antagonist (α-antagonist), which can optionally besubstituted with at least one NO or NO₂ moiety, and a compound thatdonates, transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO⁻), or as the neutral species, nitricoxide (NO.).

Another embodiment of this aspect is one where the a-blocker is notsubstituted with at least one NO or NO₂ moiety. Additional a-blockersthat are suitable for this embodiment include amines, such as tedisamil,mirtazipine, setiptiline, reboxitine and delequamine; amides, such asindoramin and SB 216469; piperizines, such as SL 89.0591, ARC 239,urapidil, 5-methylurapidil and monatepil. Indoramin is a selective,competitive α₁-antagonist that has been used for the treatment ofhypertension. Urapidil is also known to be a selective α₁-adrenergicantagonist that has a hypotensive effect in humans.

The compounds that donate, transfer or release nitric oxide or thatelevate levels of endogenous EDRF can be any of those known in the art,including those mentioned and/or exemplified below.

Nitrogen monoxide can exist in three forms: NO⁻ (nitroxyl), NO. (nitricoxide) and NO⁺ (nitrosonium). NO. is a highly reactive short-livedspecies that is potentially toxic to cells. This is critical because thepharmacological efficacy of NO depends upon the form in which it isdelivered. In contrast to NO., nitrosonium and nitroxyl do not reactwith O₂ or O₂ ⁻ species, and are also resistant to decomposition in thepresence of redox metals. Consequently, administration of NO equivalentsdoes not result in the generation of toxic by-products or theelimination of the active NO moiety.

Compounds contemplated for use in the invention are nitric oxide andcompounds that release nitric oxide or otherwise directly or indirectlydeliver or transfer nitric oxide to a site of its activity, such as on acell membrane, in vivo. As used herein, the term “nitric oxide”encompasses uncharged nitric oxide (NO.) and charged nitric oxidespecies, particularly including nitrosonium ion (NO⁺) and nitroxyl ion(NO⁻). The reactive form of nitric oxide can be provided by gaseousnitric oxide. The nitric oxide releasing, delivering or transferringcompounds, having the structure F—NO wherein F is a nitric oxidereleasing, delivering or transferring moiety, include any and all suchcompounds which provide nitric oxide to its intended site of action in aform active for their intended purpose. As used herein, the term “NOadducts” encompasses any of such nitric oxide releasing, delivering ortransferring compounds, including, for example, S-nitrosothiols,S-nitrothiols, O-nitrosoalcohols, O-nitroalcohols, sydnonimines,2-hydroxy-2-nitrosohydrazines (NONOates),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexene amines or amides,nitrosoamines, as well substrates for the endogenous enzymes whichsynthesize nitric oxide. It is contemplated that any or all of these “NOadducts” can be mono- or poly-nitrosylated or nitrosated at a variety ofnaturally susceptible or artificially provided binding sites for nitricoxide or derivatives which donate or release NO.

One group of such NO adducts is the S-nitrosothiols, which are compoundsthat include at least one —S—NO group. Such compounds includeS-nitrosopolypeptides (the term “polypeptide” includes proteins and alsopolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars, S-nitrosylated modifiedand unmodified oligonucleotides (preferably of at least 5, and moreparticularly 5-200 nucleotides); and S-nitrosylated hydrocarbons wherethe hydrocarbon is a branched or straight, saturated or unsaturated,aliphatic or aromatic hydrocarbon; S-nitrosylated hydrocarbons havingone or more substituent groups in addition to the S-nitroso group; andheterocyclic compounds. S-nitrosothiols and methods for preparing themare described in U.S. Pat. No. 5,380,758; Oae et al., Org. Prep. Proc.Int., 15(3):165-198 (1983); Loscalzo et al., J. Pharmacol. Exp. Ther.,249(3):726-729 (1989) and Kowaluk et al., J. Pharmacol. Exp. Ther.,256:1256-1264 (1990), the disclosures of which are incorporated byreference herein in their entirety.

One particularly preferred embodiment of this aspect relates toS-nitroso amino acids where the nitroso group is linked to a sulfurgroup of a sulfur-containing amino acid or derivative thereof. Suchcompounds include, for example, S-nitroso-N-acetylcysteine,S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine andS-nitroso-glutathione.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur groups on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator (TPA) andcathepsin B; transport proteins, such as lipoproteins, heme proteinssuch as hemoglobin and serum albumin; and biologically protectiveproteins, such as the immunoglobulins and the cytokines. Suchnitrosylated proteins are described in WO 93/09806, the disclosure ofwhich is incorporated herein by reference in its entirety. Examplesinclude polynitrosylated albumin where multiple thiol or othernucleophilic centers in the protein are modified.

Other suitable S-nitrosothiols include, for example:

(i) CH₃(C(R_(e))(R_(f)))_(x)SNO

(ii) HS(C(R_(e))(R_(f)))_(x)SNO

(iii) ONS(C(R_(e))(R_(f)))_(x)B; and

(iv) H₂N—CH(CO₂H)—(CH₂)_(x)—C(O)NH—C(CH₂SNO)—C(O)NH—CH₂₋CO₂H

wherein x equals 2 to 20; R_(e) and R_(f) are as defined above; and B isa fluoro, a C₁-C₆ alkoxy, a cyano, a carboxamido, a cycloalkyl, anarylalkoxy, an alkylsulfinyl, an arylthio, an alkylamino, adialkylamino, a hydroxy, a carbamoyl, a N-alkylcarbamoyl, aN,N-dialkylcarbamoyl, an amino, a hydroxyl, a carboxyl, a hydrogen, anitro or an aryl.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5 to yield the S-nitrosoderivative. Acids which may be used for this purpose include aqueoussulfuric acid, acetic acid and hydrochloric acid. Alternatively, theprecursor thiol may be nitrosylated by treatment with an alkyl nitritesuch as tert-butyl nitrite.

Another group of such NO adducts are those wherein the compounds donate,transfer or release nitric oxide, and include compounds comprising atleast one ON—O-, ON—N- or ON—C-group. The compound that includes atleast one ON—N—- or ON—C-group is preferably selected from the groupconsisting of ON—N- or ON—C-polypeptides (the term “polypeptide”includes proteins and also polyamino acids that do not possess anascertained biological function, and derivatives thereof); ON—N— orON—C-amino acids (including natural and synthetic amino acids and theirstereoisomers and racemic mixtures); ON—N- or ON—C-sugars; ON—N- orON—C-modified and unmodified oligonucleotides (preferably of at least 5,and more particularly 5-200 nucleotides); ON—O-, ON—N- orON—C-hydrocarbons which can be branched or straight, saturated orunsaturated, aliphatic or aromatic hydrocarbons; ON—N- orON—C-hydrocarbons having one or more substituent groups in addition tothe ON—N- or ON—C-group; and ON—N- or ON—C-heterocyclic compounds.

Another group of such NO adducts is the nitrites which have an —O—NOgroup wherein the organic template to which the nitrite group isappended is a protein, polypeptide, amino acid, carbohydrate, branchedor straight and saturated or unsaturated alkyl, aryl or a heterocycliccompound. A preferred example is the nitrosylated form of isosorbide.Compounds in this group form S-nitrosothiol intermediates in vivo in therecipient human or other animal to be treated and can therefore includeany structurally analogous precursor R—O—NO of the S-nitrosothiolsdescribed above.

Another group of such adducts are nitrates which donate, transfer orrelease nitric oxide and include compounds comprising at least oneO₂N—O-, O₂N—N-, O₂N—S- or O₂N—C-group. Preferred among these are thoseselected from the group consisting of O₂N—O-, O₂N—N-, O₂N—S- orO₂N—C-polypeptides; O₂N—O-, O₂N—N-, O₂N—S- or O₂N-amino acids; O₂N—O-,O₂N—N-, O₂N—S- or O₂N-sugars; O₂N—O-, O₂N—N-, O₂N—S- or O₂N—C-modifiedand unmodified oligonucleotides (preferably of at least 5, and moreparticularly 5-200 nucleotides); O₂N—O-, O₂N—N-, O₂N—S- orO₂N—C-hydrocarbons which can be branched or straight, saturated orunsaturated, aliphatic or aromatic hydrocarbons; O₂N—O-, O₂N—N-, O₂N—S-or O₂N—C-hydrocarbons having one or more substituent groups in additionto the O₂N—O-, O₂N—N-, O₂N—S- or O₂N—C-group; and O₂N—O-, O₂N—N-, O₂N—S-or O₂N—C-heterocyclic compounds. Preferred examples are isosorbidedinitrate and isosorbide mononitrate.

Another group of such NO adducts is the nitroso-metal compounds whichhave the structure (R)_(u)—A—M—(NO)_(v). R includes polypeptides (theterm “polypeptide” includes proteins and also polyamino acids that donot possess an ascertained biological function, and derivativesthereof); amino acids (including natural and synthetic amino acids andtheir stereoisomers and racemic mixtures and derivatives thereof);sugars; modified and unmodified oligonucleotides (preferably of at least5, and more particularly 5-200 nucleotides); and a hydrocarbon where thehydrocarbon is branched or straight, saturated or unsaturated, aliphaticor aromatic hydrocarbon; hydrocarbons having one or more substituentgroups in addition to the A-nitroso group; and heterocyclic compounds. Ais S, O, or N; and u and v are each independently an integer of 1, 2 or3, and M is a metal, preferably a transition metal, including, forexample, iron, copper, manganese, cobalt, selenium and lithotome. Alsocontemplated are N-nitrosylated metal centers such as nitroprusside.

Another group of such adducts are N-oxo-N-nitrosoamines which donate,transfer or release nitric oxide and have a R₁R₂—N(O—M⁺)—NO groupwherein R₁ and R₂ each independently include polypeptides, amino acids,sugars, modified and unmodified oligonucleotides, hydrocarbons where thehydrocarbon is branched or straight, saturated or unsaturated, aliphaticor aromatic hydrocarbon, hydrocarbons having one or more substituentgroups and heterocyclic compounds. M⁺ is a metal cation, such as, forexample, a Group I metal cation.

Another group of such adducts are thionitrates which donate, transfer orrelease nitric oxide and have the structure R₁₀—S—NO₂ wherein R₁₀ is asdescribed above by R₁ for the N-oxo-N-nitrosoamines.

The present invention is also directed to compounds that elevate levelsof endogenous endothelium-derived relaxing factor (EDRF) and/orstimulate endogenous NO synthesis. Such compounds include, for example,L-arginine and OH-arginine. EDRF is a vascular relaxing factor secretedby the endothelium, and has been identified as nitric oxide (NO) or aclosely related derivative thereof. (Palmer et al, Nature, 327:524-526(1987), Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).

When administered in vivo, the nitric oxides described herein may beadministered in combination with pharmaceutical carriers and in dosagesdescribed herein.

In another aspect the invention provides a method of treating and/orpreventing sexual dysfunctions or improving and/or enhancing sexualresponses in an individual in need thereof by administering to theindividual a therapeutically effective amount of a compositioncomprising at least one nitrosated and/or nitrosylated α-antagonist ofthe invention in a pharmaceutically acceptable carrier.

In another aspect the invention provides a method of treating and/orpreventing sexual dysfunctions or improving and/or enhancing sexualresponses in an individual in need thereof comprising administering tothe individual a therapeutically effective amount of a compositioncomprising at least one α-adrenergic receptor antagonist (α-antagonist),which is optionally substituted with at least one NO or NO₂ moiety, andat least one compound that donates, transfers or releases nitric oxideor elevates levels of endogenous EDRF in a pharmaceutically acceptablecarrier.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from about 1 to about 100 mg/kg body weightdaily and more usually about 3 to 30 mg/kg. Dosage unit compositions maycontain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon theanimal or individual treated and the particular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used and whether thecompound is administered as part of a drug combination. Thus, the dosageregimen actually used may vary widely and therefore may deviate from thepreferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches oriontophoresis devices. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally used as a solvent or suspending medium. For thispurpose any bland fixed oil may be used including synthetic mono- ordiglycerides, in addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, granules and gels. In such solid dosage forms,the active compound may be admixed with at least one inert diluent suchas sucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds which are known to be effective against thespecific disease state that one is targeting for treatment. Thecompositions of the invention can be administered as a mixture of anα-antagonist and a nitric oxide donor, or they can also be used incombination with one or more compounds which are known to be effectiveagainst the specific disease state that one is targeting for treatment.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compositions of the invention. Associated with suchkit(s) or container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

EXAMPLES

The following examples are presented for illustration only, and are notintended to limit the scope of the invention or appended claims.

Example 1 N—(N—L-γ-glutamyl-S-Nitroso-L-cysteinyl)glycine

N—(N—L-γ-glutamyl-L-cysteinyl)glycine (100 g, 0.325 mol) was dissolvedin deoxygenated water (200 ml) and 2N HCl (162 ml) at room temperatureand then the reaction mixture was cooled to 0° C. With rapid stirring, asolution of sodium nitrite (24.4 g, 0.35 mol) in water (40 ml) wasadded. Stirring with cooling of the reaction mixture was continued forapproximately 1 hour after which time the pink precipitate which formedwas collected by vacuum filtration. The filter cake was resuspended inchilled 40% acetone-water (600 ml) and collected by vacuum filtration.The filter cake was washed with acetone (2×200 ml) and ether (100 ml)and then dried under high vacuum at room temperature in the dark toafford the title compound as a pink powder. ¹H NMR (D₂O) δ: 1.98 (m,2H), 2.32 (t, 2H), 3.67 (t, 1H), 3.82 (s 2H), 3.86 (dd, 1H), 3.98 (dd,1H), 4.53 (m, 1H).

Example 22-Acyl-17α(3-methyl-3-nitrosothiolbutoxy)yohimban-16α-carboxylic acidmethyl ester hydrochloride salt

2a. 3-Methyl-3-(2-tetrahydropyranyl)thiobutyric acid

3-Methyl-3-thiobutyric acid (4.2 g, 31 mmol), dihydropyran (2.8 ml, 31mmol), and 200 μl of 4 N HCl/Et₂O were allowed to stand at roomtemperature overnight. The volatiles were evaporated in vacuo (2 mm Hg)yielding 6.6 g (30 mmol) of material which was used without furtherpurification. ¹H-NMR (CDCl₃): δ4.92 (d, J=8.1 Hz, 1H), 4.09 (d, J=10.5Hz, 1H), 3.49-3.56 (mult, 1H), 2.73 (dd, J=1.2 and 13.7 Hz, 1H), 2.64(d, J=13.8 Hz, 1H), 1.84-1.89 (mult 2H), 1.55-1.69 (mult, 4H), 1.51 (s,3H), 1.42 (s, 3H).

2b. 3,3′-Methyl-3,3′(2-tetrahydropyranyl)thiobutyric acid anhydride

The product of Example 2a (1.1 g, 5 mmol) and triethylamine (710 μl, 5mmol) was dissolved in ethyl acetate (50 ml) and cooled to 0° C.Triphosgene (250 mg, 0.85 mmol) was added all in one portion and thereaction was stirred at 0° C. for 15 minutes then warmed to roomtemperature with continued stirring for 30 min. The precipitate whichformed was removed by filtration and the filtrate was concentrated byrotary evaporation to afford 1.0 g (5 mmol) of the title compound.¹H-NMR (CDCl₃): δ5.03-5.06 (mult, 2H), 4.04-4.08 (mult, 2H), 3.46-3.51(mult, 2H), 2.89 (d, J=15.7 Hz, 2H), 2.77 (d, J=15.6 Hz, 2H), 1.79-1.88(mult, 4H), 1.51-1.67 (mult, 8H), 1.54 (s, 6H), 1.49 (s, 6H).

2c. 17α(3-methyl-3-tetrahydropyranylthiolbutoxy)yohimban-16α-carboxylicacid methyl ester

To a solution of yohimbine (1.6 g, 4.5 mmol) in pyridine (6 ml) wasadded the product of Example 2b (2.5 g, 6 mmol) and4-dimethylaminopyridine (730 mg, 6 mmol). The reaction mixture wasstirred at room temperature for 6 days. Acetonitrile (50 ml) was addedto the reaction and then all of the volatile components were evaporatedin vacuo. The residue was dissolved in ethyl acetate (100 ml) and washedwith a 10% solution of aqueous sodium carbonate. The aqueous wash wasthen back extracted once with ethyl acetate. The combined organicextracts were washed with H₂O, brine, and then dried over anhydroussodium sulfate. Treatment of the solution with activated charcoalfollowed by filtration and concentration of the filtrate in vacuo gave2.8 g of a dark syrup.

Chromatography on silica gel eluting with 1:1 hexane/ethyl acetatecontaining 1% by volume triethylamine afforded 670 mg (20%) of the titlecompound. ¹H-NMR (CDCl₃): δ7.76 (s, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.29(dd, J=1.0 and 7.0 Hz, 1H), 7.12 (ddd; J=1.3, 7.1, and 7.1 Hz; 1H), 7.07(ddd; J=1.1, 7.2, and 7.2 Hz; 1H), 5.46 (d, J=2.6 Hz, 1H), 5.07-5.11(mult, 1H), 4.06-4.11 (mult, 1H), 3.69 (s, 3H), 3.47-3.55 (mult, 1H),3.39 (d, J=10.4 Hz, 1H), 3.02-3.12 (mult, 2H), 2.97 (dd, J=4.5 and 12.2Hz, 1H), 2.80 (d, J=14.3 Hz, 1H), 2.71 (mult, 1H), 2.69 (d, J=13.2 Hz,1H), 2.61-2.65 (mult, 1H), 2.39 (dd, J=2.6 and 11.6 Hz, 1H), 2.23-2.33(mult, 2H), 1.71-12.07 (mult, 5H), 1.58-1.69 (mult, 8H), 1.51 (s, 3H),1.49 (s, 3H). Anal Calcd for (C₃₁H₄₂N₂O5S-1/2 H₂O): C, 66.05; H, 7.69;N, 4.97; S, 5.69. Found C, 65.74; H, 7.33; N, 4.88; S, 5.57.

2d. 2-Acyl-17α(3-methyl-3-thiolbutoxy)yohimban-16α-carboxylic acidmethyl ester

The product of Example 2c (620 mg, 1.1 mmol) was refluxed in a mixtureof acetic acid (5 ml) and acetyl chloride (5 ml) for 4 hours. Thesolvent was evaporated in vacuo (2 mm Hg). The residue was partitionedbetween 5% aqueous ammonium hydroxide and ethyl acetate. The aqueouswash was extracted with ethyl acetate. The combined organic extractswere washed with brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated in vacuo and the residue was chromatographed onsilica gel eluting with 1:1 hexane/ethyl acetate containing 1% by volumetriethylamine to afford 210 mg (34%) of2-acyl-17u.(3-methyl-3-thioacetylbutoxy)yohimban-16α-carboxylic acidmethyl ester. This diacetate (180 mg, 0.32 mmol) was dissolved in aceticacid (4 ml) to which was added mercuric trifluoroacetate (190 mg, 0.45mmol) and the reaction mixture was stirred at room temperature for 2hours. The volatiles were evaporated in vacuo leaving a gum which wastriturated with 1N HCl (6 ml) to afford a yellow powder. The powder waspartitioned between ethyl acetate and 10% aqueous ammonium hydroxide.The organic phase was filtered through Celite to remove the gray solidwhich was present and then the filtrate was washed with brine and thendried over anhydrous sodium sulfate.

Evaporation of the volatiles in vacuo afforded a solid which waschromatographed on silica gel eluting with a gradient of with 1:1hexane/ethyl acetate containing 1% by volume triethylamine to ethylacetate containing 1% by volume triethylamine to yield 60 mg (37%) ofthe title compound as a white powder. ¹H-NMR (CDCl₃): δ7.81 (d, J=7.0Hz, 1H), 7.41 (d, J=6.8 Hz, 1H), 7.23-7.29 (mult, 2H), 5.46 (s, 1H),4.17 (d, J=9.9 Hz, 1H), 3.64 (s, 3H), 3.11-3.15 (mult, 1H), 3.00 (dd,J=3.5 and 12.4 Hz, 1H), 2.64-2.84 (mult, 10H), 2.31 (dd, J=2.6 and 11.7Hz, 1H), 2.24 (d, J=12.7 Hz, 1H), 2.04-2.08 (mult, 2H), 1.41-1.62 (mult,11H). ¹³C-NMR (CDCl₃): δ171.6, 170.7, 169.5, 137.3, 136.4, 129.6, 124.1,122.9, 118.3, 117.2, 114.6, 70.0, 61.0, 59.8, 51.9, 51.8, 50.9, 47.7,45.6, 37.8, 37.6, 36.22, 36.2, 33.2, 29.9, 27.1, 23.8, 22.3.

2e. 2-Acyl-17α(3-methyl-3-nitrosothiolbutoxy)yohimban-16α-carboxylicacid methyl ester hydrochloride salt

To a slurry of the compound of Example 2d (40 mg, 0.078 mmol) in 1:1methanol/1 N HCl (4 ML) with dimethylformamide (400 μl) was added asolution of sodium nitrite (11 mg, 0.16 mmol) in H₂O (200 μl). The whitepowder turned green as the slurry was stirred at room temperature for 25minutes. At this juncture dimethylformamide (600 μl) and additionalaqueous sodium nitrite (11 mg in 200 μl of H₂O) was added and stirringat room temperature was continued for an additional 15 minutes. Thereaction mixture was partitioned between CHCl₃ and H₂O adding 10%aqueous ammonium hydroxide to the aqueous phase until basic to pH paper.The aqueous layer was extracted with CHCl₃ and the combined organicextracts were washed with brine and then dried over anhydrous sodiumsulfate. The volatiles were evaporated in vacuo and the residue wasdissolved in ether. The product was precipitated with ethereal HCl toafford 19 mg of the title compound as a green solid. ¹H-NMR (CDCl₃):δ7.81 (dd, J=1.7 and 6.8 Hz, 1H), 7.42 (d, J=6.8 Hz, 1H), 7.23-7.29(mult, 2H), 5.43 (d, J=2.6 Hz, 1H), 4.15 (d, J=9.8 Hz, 1H), 3.63 (s,3H), 3.36 (d, J=15.1 Hz, 1H), 3.30 (d, J=15.1 Hz, 1H), 3.12 (dd, J=4.9and 11.0 Hz, 1H), 3.00 (dd, J=3.7 and 12.3 Hz, 1H), 2.72 (s, 3H),2.63-2.82 (mult, 3H), 2.31 (dd, J=2.6 and 11.7 Hz, 1H), 2.03 (s, 3H),2.00 (s, 3H), 1.0-2.0 (mult, 9H).

Example 3 2-((β-(4-(3-S-Nitroso-3-methyl-butyricacid)phenyl)ethyl)aminomethyl)-1-tetralone ester hydrochloride

3a.2-((β-(4-Hydroxyphenyl)ethyl)t-butoxycarbonylaminomethyl)-1-tetralone

2-((β-(3-(4-Hydroxyphenyl)ethyl)aminomethyl))-1-tetralone (3.39 g, 11.5mmol) was dissolved in dichloromethane (50 mL) anddi-tert-butyldicarbonate (2.50 g, 11.5 mmol) was added. The reactionmixture was stirred for 100 minutes at room temperature. The solvent wasevaporated, and the residue was purified by flash chromatography onsilica-gel, eluting with hexane/ethyl acetate (3:1) to give 2.32 g (51%)of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ1.44 (s, 9H), 1.61-1.89(m, 1H), 2.15-2.29 (m, 1H), 2.50-2.85 (m, 4H), 2.90-3.08 (m, 2H),3.29-3.45 (m, 3H), 3.49-3.64 (m, 1H), 6.76 (d, 2H), 7.04 (d, 2H),7.19-7.32 (m, 2H), 7.39-7.50 (m, 1H), 8.01 (d, 1H).

3b. 2-((δ-(4-(3-Tetrahydropyranylthio-3-methyl-butyricacid)phenyl)ethyllaminomethyl)-1-tetralone ester

The product of Example 3a (0.300 g, 0.76 mmol) was dissolved in pyridine(0.5 mL) and a solution of3,3-O-ditetrahydropyranthio-3,3-O-dimethylbutanoic anhydride (0.397 g,0.95 mmol) in pyridine (0.5 mL) was added. The resulting solution wasstirred for 18 hours at room temperature. The solvent was evaporated,and the residue was purified by flash chromatography on silica-gel,eluting with hexane/ethyl acetate (4:1) to give 0.332 g (73%) of thetitle compound. ¹H-NMR (CDCl₃, 300 MHz) δ1.44 (s, 9H), 1.56 (d, 6H),1.52-1.78 (m, 6H), 1.66-1.97 (m, 1H), 2.16-2.31 (m, 1H), 2.73-3.06 (dd,overlapping with multiplet, 7H), 3.33-3.67 (m, 5H), 4.05-4.17 (m, 1H),5.09-5.17 (m, 1H), 7.01 (d, 2H), 7.13-7.36 (m, 4H), 7.47 (t, 1H), 8.01(d, 1H).

3c. 2-((β-(4-(3-Mercapto-3-methyl-butyricacid)phenyl)ethyl)-t-butoxycarbonylaminomethyl)-1-tetralone ester

The product of Example 3b (0.192 g, 0.32 mmol) was dissolved in methanol(2 mL) and a solution of silver nitrate (0.117 g, 0.69 mmol) in water(0.4 mL) was added. The resulting mixture was stirred for 1 hour at roomtemperature. The solvent was evaporated, the residue was suspended inacetone/water (1:10) and 1N HCl (1 mL) was added. After stirring for 18hours at room temperature, the precipitate was filtered and filtrate wasextracted with dichloromethane. The organic layer was washed with brine,dried over anhydrous sodium sulfate and concentrated in vacuo to give0.085 g (51%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ1.44 (s,9H), 1.58 (d, 6H), 1.73-1.96 (m, 1H), 2.17-2.31 (m, 1H), 2.38 (s, 1H),2.64-2.93 (m, 5H), 2.94-3.07 (m, 2H), 3.45 (t, 3H), 3.58-3.67 (m, 1H),7.02 (d, 2H), 7.15-7.36 (m, 4H), 7.47 (t, 1H), 8.01 (d, 1H).

3d. 2-((β-(4-(3-Mercapto-3-methyl-butyricacid)phenyl)ethyl)aminomethyl)-1-tetralone ester

The product of Example 3c (0.149 g, 0.29 mmol) was dissolved indichloromethane (3 mL) and trifluoroacetic acid (3 mL) was added. Theresulting solution was stirred for 15 minutes at room temperature. Thesolvent was evaporated and the residue was dissolved in dichloromethane(10 mL). Water (5 mL) was added and pH was made basic with saturatedsodium bicarbonate solution. Organic layer was separated and aqueousfraction was extracted with dichloromethane. The combined organic phasewas washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo to give 0.098 g (82%) of the title compound. ¹HNMR (CDCl₃, 300 MHz) δ159 (s, 6H), 1.84-2.03 (m, 1H), 2.15-2.26 (m, 1H),2.39 (s, 1H), 2.82-3.16 (m, 11H), 7.06 (d, 2H), 7.18-7.35 (m, 4H), 7.49(t, 1H), 8.00 (1H).

3e. 2-((β-(4-(3-S-Nitroso-3-methyl-butyricacid)phenyl)ethyl)aminomethyl)-1-tetralone ester hydrochloride

The product of Example 3d (0.081 g, 0.20 mmol) was dissolved in methanol(4 mL) and 1N HCl was added. A solution of sodium nitrite (0.045 g, 0.65mmol) in water (0.25 mL) was added. After stirring for 15 minutes atroom temperature an additional sodium nitrite (0.045 g, 0.65 mmol) inwater (0.25 mL) was added. The reaction mixture was stirred for 15 moreminutes, and was then extracted with dichloromethane. The organic layerwas dried over anhydrous sodium sulfate and the solvent was evaporatedto give 0.072 g (81%) of the title compound as a green solid. ¹H NMR(CDCl₃, 300 MHz) δ1.72-1.93 (m, 1H), 2.09 (s, 6H), 2.18-12.30 (m, 1H),2.84-3.11 (m, 1H), 3.14-3.33 (m, 6H), 3.36-3.57 (m, 4H), 7.03 (d, 2H),7.18-7.42 (m, 4H), 5.53 (t, 1H), 7.94 (d, 1H).

Example 44(2-methoxyphenyl-α-((1-napthalenyloxy)methyl)-1piperazineethyoxy-(3-S-nitroso-3-methyl-butyricacid) ester

4a. 3-Methyl-3-(2,4,6-trimethoxyphenylmethylthio)butyric acid

To a solution of 3-mercapto-3-methylbutyric acid (Sweetman et al, J. MedChem., 14:868 (1971), the disclosure of which is incorporated herein byreference in its entirety) (4.6 g, 34 mmol) in methylene chloride (250mL) under nitrogen and cooled over ice/salt to 5° C. (internaltemperature) was added trifluoroacetic acid (82 g, 0.72 mol). Nosignificant temperature rise was noted during the addition. To this wasthen added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (Munsonet al., J. Org. Chem., 57, 3013 (1992), the disclosure of which isincorporated herein by reference in its entirety) (6.45 g, 32 mmol) inmethylene chloride (150 mL) such that the reaction temperature does notrise above 5° C. After the addition was complete, the mixture wasstirred for an additional 5 minutes at 5° C. and the volatiles wereevaporated in vacuo (toluene or ethyl acetate can be used to assist inthe removal of volatile material). The residue was partitioned betweendiethyl ether and water and the organic phase dried over anhydroussodium sulfate, filtered and the volatile material evaporated in vacuo.The residue was treated with activated charcoal and recrystallized fromdiethyl ether/hexane. The product was isolated as a white solid in 70%yield (7 g) mp 103-105° C. ¹H NMR(CDCl₃) δ6.12 (s, 2H), 3.80-3.85 (m,11H), 2.74 (s, 2H), 1.47 (s, 6H). ¹³C NMR (CDCl₃) δ173.9, 160.6, 158.6,105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.

4b.4-(2-methoxyphenyl)-α-((1-naphthalenyloxy)methyl)-1-piperazineethyoxy-(3-(2,4,6-trimethyoxybenzylthio)-3-methyl-butyricacid) ester

Under a nitrogen atmosphere,4-(2-methoxyphenyl)-α-((1-naphthalenyloxy)methyl)-1-piperazineethanol(0.130 g, 0.35 mmol) was dissolved in anhydrous dimethylformamide (2 mL)and 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, followed bythe product of Example 4a (0.211 g, 0.69 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.132 g, 0.69 mmol). Theresulting mixture was stirred 2 hours at room temperature and then 24hours at 50° C. The solvent was evaporated in vacuo and the residue waspurified by flash chromatography on silica gel eluting with hexane/ethylacetate (3:1) to (2:1) to give the title compound (0.133 g, 56% yield).¹H NMR (CDCl₃, 300 MHz) δ1.49-1.53 (d, 6H, J=2.42 Hz), 2.70-2.84 (m,8H), 2.98-3.09 (m, 4H), 3.75-3.85 (m, 11H), 3.86 (s, 3H), 4.31-4.36 (m,2H), 5.43-5.52 (m, 1H), 6.08 (s, 2H), 6.81-6 86 (m, 2H), 6.90-6.93 (m.2H), 6.97-7.01 (m, 1H), 7.33-7.7 (m, 4H), 7.77-7.82 (m, 1H), 8.23-8.27(m, 1H).

4c.4-(2-methoxyphenyl)-α-((1-naphthalenyloxy)methyl)-1-piperazineethyoxy-(3-mercanto-3-methyl-butyricacid) ester

The product of Example 4b (0.128 g, 0.186 mmol) was dissolved inmethylene chloride (0.50 mL), and then anisole (0.13 mL, 1.20 mmol),phenol (0.013 g, 0.14 mmol), water (0.13 mL), and trifluoroacetic acid(0.80 mL, 10.4 mmol) were added. After 1 hour of stirring at roomtemperature, toluene (2 mL) was added and volatiles were evaporated. Theresidue was purified by flash chromatography on silica gel eluting withhexane/ethyl acetate (2:1) to give the title compound (0.055 g, 60%yield) as a solid. ¹H NMR (CDCl₃, 300 MHz) δ1.49-1.53 (d, 6H, J=2.42Hz), 2.59 (s, 1H), 2.69-2.86 (m, 8H), 3.01-3.09 (m, 4H), 3.86 (s, 3H),4.26-4.39 (m, 2H), 5.53-5.63 (m, 1H), 6.81-6.88 (d, 2H, J=7.5 Hz),6.90-6 95 (m, 2H), 6.98-7.04 (m, 1H), 7.34-7.40 (t, 1H, J=7.5 Hz),7.43-7.78 (m, 3H), 7.79-7.82 (m, 1H), 8.23-8.26 (m, 1H).

4d.4-(2-methoxyphenyl)-α-((1-naphthalenyloxy)methyl)-1-piperazineethyoxy-(3-S-nitroso-3-methyl-butyricacid) ester

The product of Example 4c (0.048 g, 0.097 mmol) was dissolved inmethanol (5 mL) and 1N solution of hydrochloric acid (1.5 mL) was added.The resulting mixture was cooled to 0° C. and a solution of sodiumnitrite (0.040 g, 0.058 mmol) in water (0.5 mL) was added. After 1 hourstirring at 0° C. the reaction mixture was extracted with methylenechloride, washed with brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated in vacuo to give the title compound (0.045 g, 82%yield) as a green solid. ¹H NMR(CDCl₃, 300 MHz) δ2.00 (s, 6H), 3.38-3.50(m, 13H), 3.88 (s, 3H), 4.31-4.40 (m, 2H), 5.91 (s, 1H), 6.79-6.95 (m,5H), 7.33-7.70 (m, 4H), 7.79-7.82 (m, 1H), 8.09-8.12 (m, 1H).

Example 52-(4-(2-Furoyl)piperazin-1-yl)-(4-(3-S-nitroso-3-methyl-butyricacid))-6,7-dimethyoxyquinazoline amide

5a.2-(4-(2-Furoyl)piperazin-1-y)-(4-(3-(2,4,6-trimethyoxybenzylthio)-3-methyl-butyricacid))-6,7-dimethyoxyquinazoline amide

Under a nitrogen atmosphere2-(4-(2-furoyl)piperazin-1-yl)-amino-6,7-dimethyoxyquinazoline (0.200 g,0.52 mmol) was dissolved in anhydrous dimethylformamide (5 mL) and4-dimethylaminopyridine (0.025 g, 0.21 mmol) was added, followed by theproduct of Example 4a (0.319 g, 1.04 mmol) and1-ethyl-3-(3dimethylaminopropyl)carbodiimide (0.199 g, 1.04 mmol). Theresulting mixture was stirred at 50° C. for 48 hours. The solvent wasevaporated in vacuo and the residue was purified by flash chromatographyon silica gel eluting with hexane/ethyl acetate (3:1) to (1:5 to give0.072 g (20% yield) of the title compound as a white solid. ¹H NMR(CDCl₃, 300 MHz) δ1.52 (s, 6H), 2.88 (s, 1H), 2.90 (s, 2H), 2.96 (s, 1),3.56 (s, 6H), 3.72 (s, 3H), 3.90-4.01 (m, 16H), 6.48-6.52 (dd, 1H,J=1.69 and 3.32 Hz), 6.94 (s, 1H), 7.01-7.05 (d, 1H, J=3.45 Hz), 7.19(s, 1H), 7.50-7.53 (m, 1H).

5b. 2-(4-(2-Furoyl)piperazin-1-yl)-(4(3-mecapto-3-methyl-butyricacid))6,7-dimethyoxyquinazoline amide

The product of Example 5a (0.160 g, 0.24 mmol) was dissolved inmethylene chloride (0.67 mL), and then anisole (0.16 mL, 1.47 nimmol),phenol (0.007 g, 0.047 nimmol), water (0.16 mL), and trifluoroaceticacid (0.67 mL, 8.63 mmol) were added. After 45 minutes of stirring atroom temperature, toluene (5 mL) was added and volatiles wereevaporated. The residue was purified by flash chromatography on silicagel eluting with methylene chloride/methanol (30:1) to (15:1) to givethe title compound (0.043 g, 36% yield) as a solid. ¹HNMR (CDCl₃, 300MHz) δ1.58 (s, 6H), 2.45 (s, 1H), 3.00 (s, 2H), 3.87-3.94 (d, 6H, J=6.28Hz), 3.92-4.06 (m, 8H), 6.53-6.57 (dd, 1H, J=1.68 and 3.41 Hz), 6.98 (s,1H), 7.15-7.18 (d, 1H, J=3.48 Hz), 7.49 (s, 1H), 7.54-7.59 (m, 1H).

5c. 2-(4-(2-Furoyl)piperazin-1-yl)-(4-(3-S-nitroso-3-methyl-butyricacid))-6,7-dimethyoxvqiuinazoline amide

The product of Example 5b (0.036 g, 0.080 mmol) was dissolved inmethanol and 1N solution of hydrochloric acid (1 mL) was added. Theresulting mixture was cooled to 0° C. and a solution of sodium nitrite(0.067 g, 0.97 mmol) in water (0.5 mL) was added. After 40 min. stirringat 0° C. the reaction mixture was extracted with methylene chloride,washed with brine and dried over anhydrous sodium sulfate. The solventwas evaporated in vacuo to give the title compound (0.023 g, 55% yield)as a green solid. ¹H NMR (CDCl₃, 300 MHz) δ2.12 (s, 6H), 3.49 (s, 2H),3.85-3.99 (m, 14H), 6.51-6.55 (dd, 1H, J=1.74 and 3.45 Hz), 6.79-6.98(m, 2H), 7.06-7.09 (d, 1H, J=3.23 Hz), 7.34-7.58 (m, 1H).

Example 64-(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol-(3-S-nitroso-3-methyl-butyricacid) ester

6a. 4-(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol4-(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol acetateester (1.00 g, 3.20 mmol) was dissolved in methanol (10 mL) and sodiumhydroxide (0.317 g, 7.92 mmol) was added. The reaction mixture wasstirred at room temperature for 10 minutes, diluted with ethyl ether (10mL) and washed with sodium bicarbonate solution. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give the title compound (0.71 g, 93% yield) as a white solid. ¹H NMR(CDCl₃, 300 MHz) δ1.10-1.13 (d, 6H, J=6.9 Hz), 2.19 (s, 3H), 2.41 (s,6H), 2.80-2.85 (t, 2H, J=3.9 Hz), 3.19-3.26 (m, 1H), 4.02-4.07 (t, 2H,J=5.9 Hz), 6.37-6.59 (d, 2H, J=3.72 Hz).

6b.4-(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol-(3-(2,4,6-trimethyoxybenzylthio))-3-methyl-butyricacid) ester

Under a nitrogen atmosphere, the product of Example 6a (0.270 g, 1.14mmol) was dissolved in anhydrous dimethylformamide (2 mL) and4-dimethylaminopyridine (0.028 g, 0.23 mmol) was added, followed by theproduct of Example 4a (0.418 g, 1.36 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.260 g, 1.36 mmol). Theresulting mixture was stirred at 55° C. for 24 hours. The solvent wasevaporated in vacuo and the residue was purified by flash chromatographyon silica gel, eluting with methylene chloride/methanol (20:1) to give0.232 g (39% yield) of the title compound. ¹H NMR (CDCl₃, 300 MHz)δ1.14-1.18 (d, 6H, J=6.9 Hz), 1.59 (s, 6H), 2.15 (s, 3H), 2.35 (s, 6H),2.72-2.77 (t, 2H, J=5.9 Hz), 2.93-2.96 (m, 2H), 3.23-3.28 (m, 1H),3.74-4.02 (m, 11H), 4.03-4.07 (t, 2H, J=5.9 Hz), 6.11 (s, 2H), 6.67 (s,1H), 6.81 (s, 1H).

6c.4-(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol-(3-mercapto-3-methyl-butyricacid) ester

The product of Example 6b (0.220 g, 0.42 mmol) was dissolved inmethylene chloride (0.30 mL) and anisole (0.22 mL, 2.02 mmol), phenol(0.022 g, 0.23 mmol), water (0.22 mL) and trifluoroacetic acid (1.0 mL,13.0 mmol) were added. After 1 hour of stirring at room temperature,toluene (5 mL) was added and volatiles were evaporated. The residue waspurified by flash chromatography on silica gel, eluting with methylenechloride/methanol (20:1) to give the title compound (0.095 g, 64%yield). ¹H NMR (CDCl₃, 300 MHz) δ1.14-1.16 (d, 6H, J=6.9 Hz), 1.58 (s,6H), 2.14 (s, 3H), 2.40 (s, 1H), 2.87-2.94 (m, 8H), 3.14-3.20 (m, 1H),3.50-3.53 (m, 2H), 4.31-4.34 (m, 2H), 6.67 (s, 1H), 6.84 (s, 1H).

6d.4-(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol-(3-S-nitroso-3-methyl-butyricacid) ester

The product of Example 6c (0.035 g, 0.10 mmol) was dissolved in methanol(5 mL) and 1N solution of hydrochloric acid (1 mL) was added. Theresulting mixture was cooled to 0° C. and a solution of sodium nitrite(0.014 g, 0.20 mmol) in water (0.7 mL) was added. After 20 minutesstirring at 0° C., an additional sodium nitrite (0.032 g, 0.46 mmol) inwater (0.7 mL) was added and the resulting mixture was stirred for 30minutes. The reaction mixture was extracted with methylene chloride,washed with brine and dried over anhydrous sodium sulfate. The solventwas evaporated in vacuo to afford the product (0.028 g, 67% yield) as agreen solid. ¹H NMR (CDCl₃, 300 MHz) δ1.13-1.17 (d, 6H, J=6.9 Hz),2.08-2.11 (m, 9H), 2.95 (s, 6H), 3.13-3.20 (m, 1H), 3.45-3.51 (m, 4H),4.43-4.46 (m, 2H), 6.23 (s, 1H), 6.70 (s, 1H), 6.76 (s, 1H).

Example 7 3-((4-5-Dihydro-1-(3-S-nitroso-3-methylbutyloxy)-imidazol-2-yl)methyl)(4-methylphenyl)amino)phenol-(3-S-nitroso-3-methyl-butyricacid) ester

7a. 3-Mercapto-3-methyl butyl acetate

3-Mercapto-3-methyl butanol (Sweetman et al, J. Med. Chem. 14:868(1971), the disclosure of which is incorporated by reference herein inits entirety) (5 g, 42 mmol) and pyridine (3.6 mL, 43 mmol) weredissolved in methylene chloride (50 mL) and cooled to −78° C. Acetylchloride (3.1 mL, 43 mmol) was added dropwise. The solution was keptcold for 30 min then allowed to warm to room temperature. Stirring wascontinued for 1.5 hr. The reaction mixture was diluted with methylenechloride, washed with 1 N HCl and brine, and dried over sodium sulfate.Evaporation of the solvent gave 6.6 g of the title compound which wasused without further purification. ¹H-NMR (CDCl₃): δ4.25 (t, J=7.1 Hz, 2H), 2.21 (s, 1H), 2.03 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 1.41 (s, 3H).

7b. 3-Tetrahydronpyranylthio-3-methyl butyl acetate

The product of Example 7a (6.6 g, 41 mmol), dihydropyran (4 mL, 44mmol), and 4 N HCl/Et₂O (1 mL) were allowed to stand at room temperaturefor 24 hours. The volatiles were evaporated in vacuo to leave the titlecompound as a viscous oil which was used without further purification.¹H-NMR (CDCl₃): δ4.97 (dd, J=3.4 and 6.6 Hz, 1H), 4.24 (t, J=7.1 Hz,2H), 4.04-4.09 (mult, 1H), 3.46-3.52 (mult, 1H), 2.03 (s, 3H), 1.93 (t,J=7.5 Hz, 2H), 1.42-1.88 (mult, 6H), 1.37 (s, 3H), 1.36 (s, 3H).

7c. 3-Tetrahydropyranylthio-3-methyl butanol

The product of Example 7b (800 mg, 3.3 mmol) and sodium bicarbonate (1.4g, 16 mmol) were dissolved in methanol (10 mL) and stirred at roomtemperature for 18 hours. The reaction mixture was diluted with ether(30 mL) to precipitate the salts and filtered through Celite.Evaporation of the solvent and chromatography on silica gel eluting with3:1 hexane/ethyl acetate gave 340 mg (51%) of the title compound. ¹H NMR(CDCl₃): δ4.92 (dd, J=3.1 and 7.6 Hz, 1H), 4.05 (ddd; J=4.0, 4.0, and11.6 Hz, 1H), 3.81 (ddd; J=6.3, 6.3, and 12.6 Hz, 1H), 3.78 (ddd; J=6.3,6.3 and 12.6 Hz, 1H), 3.49 (ddd; J=3.8, 7.7, and 11.8 Hz, 1H), 1.79-1.89(mult, 4H), 1.60-1.67 (mult, 4H), 1.56 (s, 3H), 1.55 (s, 3H). Anal calcdfor C₁₀H₂₀O₂S: C, 58.78; H, 9.87; S, 15.69. Found C, 58.42; H, 9.73; S,15.58.

7d. 3-((4,5-Dihydro-1-(3-tetrahydropyranylthio-3-methylbutyloxy)-imidazol-2-yl)methyl)amino]phenol-(3-tetrahydropyranylthio-3-methyl-butyricacid) ester

The product of Example 7c (700 mg, 3.5 mmol) was dissolved intetrahydrofuran (5 mL) and cooled to −78° C. To this solution was added2.5 M BuLi (1.38 mL, 3.5 mmol), and the reaction mixture was stirred at−78° C. for 20 minutes. A solution of 1.93 M phosgene in toluene (3.6mL, 7.0 mmol) was cooled to −78° C. and the cold solution of lithiumalkoxide was rapidly cannulated into the phosgene solution. The reactionmixture was stirred at −78° C. for 30 minutes and then warmed to roomtemperature and stirred for 2 hours. The solution was filtered through acotton plug and concentrated to give the chloroformate as a syrup. Aslurry of3-((4,5-dihydro-1H-imidazol-2-yl)methyl)(4-methylphenyl)amino)phenolhydrochloride (500 mg, 1.6 mmol) and triethylamine (650 μL, 4.7 mmol) inmethylene chloride (10 mL) was cooled to −78° C. The chloroformate wasdissolved in methylene chloride (4 mL) and this solution was added tothe slurry. The resulting reaction mixture was stirred at −78° C. for 30minutes and was then warmed to room temperature and stirred for 20hours. The reaction mixture was diluted with methylene chloride and thenwashed successively with 0.1 N HCl, saturated aqueous sodiumbicarbonate, and brine; followed by drying over sodium sulfate.Evaporation of the solvent and chromatography on silica gel eluting with2:1 hexane/ethyl acetate gave 540 mg (46%) of the title compound. ¹H NMR(CDCl₃): δ7.18 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.12 (t, J=8.2Hz. 1H), 6.57-6.62 (mult, 2H), 6.51 (t, J=2.2 Hz, 1H), 4.94-4.99 (mult.2 H), 4.89 (s, 2H), 4.38 (t, J=7.3 Hz, 2H), 4.32 (t, J=7.1 Hz, 2H),4.03-4.08 (mult, 2H), 3.79 (s, 4H), 3.46-3.52 (mult, 2H), 2.32 (s, 3H),1.51-2.05 (mult, 16H).

7e. 3-((4,5-Dihydro-1-(3-thiol-3-methylbutyloxy)-imidazol-2-yl)methyl)(4-methylphenyl)amino)phenol-(3-thiol-3-methyl-butyricacid) ester

The product of Example 7d (400 mg, 0.54 mmol), mercaptoethanol (760 μL,10 mmol), and 4 N HCl in ether (250 μL, 1 mmol) were kept at roomtemperature for 24 hours. The reaction mixture was diluted with ethylacetate and then washed with saturated aqueous sodium bicarbonate,water, and brine, and then dried over sodium sulfate. Hydrochloric acidwas added and the solvent was evaporated to leave a syrup. The syrup wastriturated with ethanol and ether. Decantation of the solvents andsubjecting the residue to high vacuum overnight afforded 130 mg ofsolid. The solid was chromatographed on silica gel eluting with 3:1hexane/ethyl acetate to give 30 mg (10%) of the title compound. ¹H NMR(CDCl₃): δ7.18 (d, J=8.6 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 7.13 (t, J=8.2Hz, 1H), 6.61 (dd, J=2.4 and 8.3 Hz, 1H), 6.59 (dd, J=2.1 and 7.9 Hz,1H), 6.52 (t, J=2.2 Hz, 1H), 4.90 (s, 2H), 4.41 (t, J=7.3 Hz, 2H), 4.35(t, J=7.0 Hz, 2H), 3.80 (s, 4H), 2.33 (s, 3H), 2.02 (t, J=7.1 Hz, 2H),1.97 (t, J=7.1 Hz, 2H), 1.76 (s, 1H), 1.75 (s, 1H), 1.43 (s, 12H).

7f. 3-((4,5-Dihydro-1-(3-S-nitroso-3-methylbutyloxy)-imidazol-2-yl)methyl)(4-methylphenyl)amino)phenol-(3-S-nitroso-3-methyl-butyric acid) ester

The product of Example 7e (18 mg, 0.033 mmol) was dissolved indimethylforamide (200 μL) and 4 N HCl in ether (25 μL, 0.1 mmol) wasadded. The reaction mixture was cooled to 0° C. and tert-butyl nitrite(12 μL, 0.12 mmol) was added and then the reaction mixture was stirredat for 0° C. for 20 minutes. The solvent was evaporated in vacuo and thesolid residue obtained was azetroped with chloroform to afford the titlecompound as a foam. ¹H NMR (DMSO-d₆): δ7.09 (d J=8.0 Hz, 1H), 6.89 (d,J=8.2 Hz, 1H), 6.61-6.72 (mult, 6H) 5.10 (br s, 2H), 4.44 (t. J=6.7 Hz,2H), 4.38 (t, J=6.7 Hz, 2H), 4.00-4.10 (mult, 2H), 3.89-4.00 (mult, 2H),2.65 (t, J=6.5 Hz, 2H), 2.62 (t, J=6.6 Hz, 2H), 2.30 (s, 3H), 1.92 (s,6H), 1.89 (s, 6H).

Example 84(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol-(4-(2-nitrosothiolcyclohexylmethylamido))butyric acid ester hydrochloride

8a.4-(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol-(4-carboxylicacid) butyric acid ester

The product of Example 6a was dissolved in anhydrous chloroform (32 mL)and glutaric anhydride (0.886 g, 7.77 mmol) was added, followed by DMAP(0.190 g, 1.56 mmol) and triethylamine (0.820 mL, 5.84 mmol). Theresulting mixture was stirred at 55° C. for 42 hours. The mixture wascooled down to room temperature and poured into dichloromethane/watermixture. The organic fraction was separated, washed with brine, driedover anhydrous sodium sulfate and concentrated in vacuo to give (1.42 g,94% yield) of the title compound as a clear oil. ¹H NMR (300 MHz, CDCl₃)δ1.13-1.18 (d, 6H), 2.04 (s, 3H), 2.04-2.13 (m, 2H), 2.38-2.44 (t, 2H),2.50 (s, 6H), 2.60-2.66 (t, 2H), 2.96-3.07 (t, 2H), 3.17-3.26 (m, 1H),4.11-4.16 (t, 2H), 6.65 (s, 1H), 6.79 (s, 1H).

8b.4-(2-Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol-(4-(2-mercaptocyclohexylmethylamido))butyric acid ester

Under a nitrogen atmosphere, the product of Example 8a (1.4 g, 3.62mmol) was dissolved in anhydrous chloroform (20 mL) and2-mercaptocyclohexylmethyl amine (0.71 g, 4.8 mmol) was added, followedby DMAP (0.195 g, 1.6 mmol). A solution of EDAC (0.764 g, 4.00 mmol) inchloroform (10 mL) was added dropwise and the resulting mixture wasstirred at 55° C. for 40 hours. Volatiles were evaporated and theresidue was purified by chromatography on silica-gel, eluting withmethylene chloride/methanol (15:1) to give (0.930 g, 54% yield) of thetitle compound as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ1.13-1.18 (d,6H), 1.42-1.68 (m, 10H), 2.10 (s, 3H), 2.10-2.13 (m, 2H), 2.36 (s, 6H),2.34-2.38 (m, 2H), 2.61-2.66 (t, 2H), 2.72-2.78 (t, 2H), 3.17-3.26 (m,1H), 3.39-3.43 (d, 2H), 4.02-4.07 (t, 2H), 6.05 (s, 1H), 6.66 (s, 1H),6.79 (s, 1H).

8c.4-(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-methylethyl)phenol-4(2-nitrosothiolcyclohexylmethylamido)butyric acid) ester hydrochloride

The product of Example 8b (0.285 g, 0.60 mmol) was dissolved indichloromethane (9 mL) and 2.9 N HCl in ether (0.06 mL) was added. Theresulting mixture was cooled to 0° C. and tert-butyl nitrite (0.300 mL,2.53 mmol) was added, followed by 2.9 NHCl in ether (0.05 mL). Thereaction mixture was stirred on ice for 45 minutes and volatiles wereevaporated. The residue was purified by chromatography on silica-gel,eluting with methylene chloride/methanol (15:1) to give the green solid.The solid was dissolved in methylene chloride/ether and treated with 2.9N HCl in ether (0.200 mL). Volatiles were evaporated under reducedpressure to give (0.164 g, 50% yield) of the title compound as a greensolid. ¹H NMR (300 MHz, CDCl₃) δ1.1-1.18 (d, 6H), 1.47-1.55 (m, 3H),1.71-1.77 (m, 3H), 2.02-2.09 (m, 7H), 2.27-2.34 (t, 2H), 2.41-2.50 (m,2H), 2.57-2.74 (t, 2H), 2.74 (s, 6H), 3.17-3.26 (m, 3H), 4.14-4.18 (d,2H), 4.30-4.34 (t, 2H), 5.75 (s, 1H), 6.68 (s, 1H), 6.80 (s, 1H).

Example 9 In Vivo Comparative Erectile Responses

Male New Zealand white rabbits weighing 2.5 kg were used as the animalmodel. Animals were first relaxed with an i.m. injection of 25 mg/kgketamine prior to anesthesia with a bolus i.v. injection of 10 mg/kgProfol and maintained with i.v. infusion at 0.5 mg/kg/min. Ventilationof the animals was performed with 1% halothane plus 0.8 L/min O₂ and 1L/min N₂O. A 22 gauge angiocatheter was placed in the femoral artery formeasurement of systemic blood pressure. A dorsal incision was made inthe penis and the corpora cavernosa exposed and cannulated with a 21gauge butterfly needle to measure intracavernosal pressure.

Drugs at various concentrations were delivered intracavernosally at avolume of 150 μl through a 25 gauge needle. A 150 μl solution of amixture of papaverine (30 mg/kg), phentolamine (1 mg/kg) andprostaglandin E1 (10 μg/ml) (pap/phent/PGE1) was injected in the corporaas a standard solution for comparison with the response of yohimbine,Example 1, Example 2, and the combination of yohimbine and Example 1.This pap/phent/PGE1 mixture is considered to cause a maximalerection-inducing effect.

As shown in FIG. 1, yohimbine dose dependently induced erectile responsein the anesthetized rabbit. A 500 μg dose of Example 1 was able toinduce near maximal response relative to the standard dose ofpap/phent/PGE1. A combination of the submaximal dose of yohimbine (150μg) and Example 1 (500 μg) also induced maximum erectile response.Yohimbine at both the submaximal and maximal efficacy doses producedvery short duration of action (FIG. 2). Example 1 produced a much longerduration of action. The duration of action is potentiated by acombination of Example 1 and yohimbine which is longer than the sum ofthe duration of each of these compounds alone (FIG. 2).

FIG. 3 shows that the compound of Example 2 at the 500 μg dose isequipotent to the standard dose of pap/phent/PGE1. A higher dose of thecompound of Example 2 (1 mg) is at least equal to or more efficaciousthan the standard dose of the pap/phent/PGE1 mixture. FIG. 4 shows thatthe compound of Example 2 has the advantage of producing longer durationof action compared to yohimbine. FIG. 5A demonstrates that a dose (500μg) of the compound of Example 2 effective in the erectile response didnot produce any effect on systemic blood pressure upon intracavernosalinjection. However, FIG. 5B demonstrates that a standard dose of themixture of pap/phent/PGE1 produced a significant decrease in systemicblood pressure upon intracavernosal injection, suggesting that thecompound of Example 2 lacks this side effect.

FIG. 6 shows that intracavernosal administration of 1 mg of Example 6 ismore efficacious than 1 mg moxisylyte in inducing the erectile responsein vivo in the anesthetized rabbit. FIG. 7 shows that a 1 mg dose ofExample 6 produces a longer duration of erectile response compared to 1mg moxisylyte. Also, FIG. 7 shows that 2 mg of Example 6 produces a muchlonger duration of action compared to 2 mg moxisylyte.

FIG. 1 shows the percent peak erectile response in vivo compared to thatproduced by 150 μl of pap/phent/PGE1 (30 mg/ml:1 mg/ml:10 μg/ml) in theanesthetized rabbit following the intracavernosal injection of 150 μl ofyohimbine (150 μg, 500 μg), the compound of Example 1 (500 μg), and acombination of yohimbine (150 μg) and the compound of Example 1 (500μg). The ordinate is the percent response of intracavernosal pressurerelative to that produced by pap/phent/PGE1 and the abscissa indicatesthe various drugs given.

FIG. 2 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavernosal administration of yohimbine(150 μg, 500 μg), the compound of Example 1 (500 μg), and a combinationof yohimbine (150 μg) and the compound of Example 1 (500 μg). Theordinate indicates the various drugs given and the abscissa is theduration in minutes.

FIG. 3 shows the percent peak erectile response in vivo compared to thatproduced by 150 μl of pap/phent/PGE1 (30 mg/ml:1 mg/ml:10 μg/ml) in theanesthetized rabbit following the intracavernosal injection of 150 μl ofyohimbine (150 μg, 500 μg and 1 mg) and the compound of Example 2 (500μg, 1 mg). The ordinate is the percent response of intracavernosalpressure relative to that produced by pap/phent/PGE1 and the abscissaindicates the various doses of yohimbine and the compound of Example 2given.

FIG. 4 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavernosal administration of yohimbine(150 μg, 500 μg and 1 mg) and the compound of Example 2 (500 μg and 1mg). The ordinate indicates the various doses of yohimbine and thecompound of Example 2 given and the abscissa is the duration in minutes.

FIG. 5A shows the effects of intracavernosal injections of Example 2(500 μg) on systemic blood pressure in the anesthetized rabbit. Forcomparison, FIG. 5B shows the effects of intracavernosal injections ofthe standard mixture of pap/phent/PGE1 on systemic blood pressure in theanesthetized rabbit.

FIG. 6 shows the percent peak erectile response in vivo compared to thatproduced by 150 μg of pap/phent/PGE1 (30 mg/ml:1 mg/ml:10 μg/ml) in theanesthetized rabbit following the intracavernosal injection ofmoxisylyte (1 mg) and the compound of Example 6 (1 mg). The ordinate isthe percent response of intracavernosal pressure relative to thatproduced by pap/phent/PGE1 and the abscissa indicates the dose ofmoxisylyte and the compound of Example 6 given.

FIG. 7 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavernosal administration of moxisylyte (1and 2 mg) and the compound of Example 6 (1 and 2 mg). The ordinateindicates the dose of moxisylyte and the compound of Example 6, and theabscissa indicates the duration in minutes.

Each of the publications, patents and patent applications describedherein is hereby incorporated by reference herein in their entirety.

Various modifications of the invention, in addition to those describedherein, will be apparent to one skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

What is claimed is:
 1. A method of treating female impotence comprisingadministering to a female individual a therapeutically effective amountof at least one compound of structure III and a pharmaceuticallyacceptable carrier, wherein the compound of structure III is:

wherein D is (i) —NO, (ii) —NO₂, (iii)—C(R_(d))—O—C(O)—Y—Z—(C(R_(e))(R_(f)))_(p)—T—Q, wherein R_(d) is ahydrogen, a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or aheteroaryl; Y is oxygen, sulfur, carbon or NR_(i) wherein R_(i) is ahydrogen or a lower alkyl; R_(e) and R_(f) are each independently ahydrogen, a lower alkyl, a haloalkyl, a cycloalkyl, an alkoxy, an aryl,a heteroaryl, an arylalkyl, an amino, an alkylamino, a dialkylamino, anamido, an alkylamido, a carboxylic acid, a carboxylic ester, acarboxamido, a carboxy or —T—Q, or R_(e) and R_(f) taken together withthe carbon atoms to which they are attached are a carbonyl, aheterocyclic ring, a cycloalkyl or a bridged cycloalkyl; p is an integerfrom 1 to 10; T is independently a covalent bond, oxygen, sulfur ornitrogen; Z is a covalent bond, a lower alkyl, a haloalkyl, acycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroalkyl, anarylheterocyclic ring or (C(R_(e))(R_(f)))_(p), and Q is —NO or —NO₂;(iv) —C(O)—Y—Z—(G—(C(R_(e))(R_(f)))_(q)—T—Q)_(p) wherein G is a covalentbond, —T—C(O)—, —C(O)—T— or T, wherein q is an integer from 0 or 5, andwherein R_(e), R_(f), p, Q, Z, Y and T are as defined above, or (v)—P—Z—(G—(C(R_(e))(R_(f)))_(q)—T—Q)_(p), wherein P is a carbonyl, aphosphoryl or a silyl, and wherein R_(e), R_(f), p, q, Q, T, Z and G areas defined above; and wherein R_(h) is a hydrogen, —C(O)—OR_(d) or—C(O)—X, wherein X is (1)—Y—(C(R_(e))(R_(f)))_(p)—G—(C(R_(e))(R_(f)))_(p)—T—Q, wherein G is acovalent bond, —T—C(O)—,—C(O)—T—, or —C(Y—C(O)—R_(m))—, wherein R_(m) isa heteroaryl or a heterocyclic ring; and wherein Y, R_(d), R_(e), R_(f),p, Q and T are as defined above; or

wherein W is a heterocyclic ring or NR_(i)R′_(i), wherein R_(i) andR′_(i) are each independently a lower alkyl, an aryl, or an alkenyl; andwherein R_(j) is —D or —(O)CR_(d), wherein D and R_(d) are as definedabove.
 2. The method of claim 1, wherein the compound of structure IIIis a nitrosated yohimbine, a nitrosylated yohimbine, a nitrosated andnitrosylated yohimbine, a nitrosated apoyohimbine, a nitrosylatedapoyohimbine, a nitrosated and nitrosylated apoyohimbine, a nitrosatedcorynanthine, a nitrosylated corynanthine, a nitrosated and nitrosylatedcorynanthine, a nitrosated β-yohimbine, a nitrosylated β-yohimbine, anitrosated and nitrosylated β-yohimbine, a nitrosated yohimbol, anitrosylated yohimbol, a nitrosated and nitrosylated yohimbol, anitrosated pseudoyohimbine, a nitrosylated pseudoyohimbine, a nitrosatedand nitrosylated pseudoyohimbine, a nitrosated epi-3α-yohimbine, anitrosylated epi-3α-yohimbine, a nitrosated and nitrosylatedepi-3α-yohimbine, a nitrosated rauwolscine, a nitrosylated rauwolscine,a nitrosated and nitrosylated rauwolscine.
 3. The method of claim 2,wherein the compound of structure III is a nitrosated yohimbine, anitrosylated yohimbine or a nitrosated and nitrosylated yohimbine. 4.The method of claim 1, wherein the at least one compound of structureIII and the pharmaceutically acceptable carrier are administered orally.5. The method of claim 1, wherein the at least one compound of structureIII and the pharmaceutically acceptable carrier are administeredparenterally.
 6. The method of claim 1, wherein the at least onecompound of structure III and the pharmaceutically acceptable carrierare administered topically.
 7. A method of treating female impotencecomprising administering to a female individual a therapeuticallyeffective amount of at least one compound of structure III and at leastone compound that donates, transfers or releases nitric oxide, elevateslevels of endogenous endothelium-derived relaxing factor or stimulatesendogenous nitric oxide synthesis; wherein the at least one compound ofstructure III is:

wherein D is (i) —NO, (ii) —NO₂, (iii)—C(R_(d))—O—C(O)—Y—Z—(C(R_(e))(R_(f)))_(p)—T—Q, wherein R_(d) is ahydrogen, a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or aheteroaryl; Y is oxygen, sulfur, carbon or NR_(i) wherein R_(i) is ahydrogen or a lower alkyl; R_(e) and R_(f) are each independently ahydrogen, a lower alkyl, a haloalkyl, a cycloalkyl, an alkoxy, an aryl,a heteroaryl, an arylalkyl, an amino, an alkylamino, a dialkylamino, anamido, an alkylamido, a carboxylic acid, a carboxylic ester, acarboxamido, a carboxy or —T—Q, or R_(e) and R_(f) taken together withthe carbon atoms to which they are attached are a carbonyl, aheterocyclic ring, a cycloalkyl or a bridged cycloalkyl; p is an integerfrom 1 to 10; T is independently a covalent bond, oxygen, sulfur ornitrogen; Z is a covalent bond, a lower alkyl, a haloalkyl, acycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroalkyl, anarylheterocyclic ring or (C(R_(e))(R_(f)))_(p), and Q is —NO or —NO₂;(iv) —C(O)—Y—Z—(G—(C(R_(e))(R_(f)))_(q)—T—Q)_(p) wherein G is a covalentbond, —T—C(O)—, —C(O)—T— or T, wherein q is an integer from 0 or 5, andwherein R_(e), R_(f), p, Q, Z, Y and T are as defined above, or (v)—P—Z—(G—(C(R_(e))(R_(f)))_(q)—T—Q)_(p), wherein P is a carbonyl, aphosphoryl or a silyl, and wherein R_(e), R_(f), p, q, Q, T, Z and G areas defined above; and wherein R_(h) is a hydrogen, —C(O)—OR_(d) or—C(O)—X, wherein X is (1)—Y—(C(R_(e))(R_(f)))_(p)—G—(C(R_(e))(R_(f)))_(p)—T—Q, wherein G is acovalent bond, —T—C(O)—, —C(O)—T—, or —C(Y—C(O)—R_(m))—, wherein R_(m)is a heteroaryl or a heterocyclic ring; and wherein Y, R_(d), R_(e),R_(f), p, Q and T are as defined above; or (2)

wherein W is a heterocyclic ring or NR_(i)R′_(i), wherein R_(i) andR′_(i) are each independently a lower alkyl, an aryl, or an alkenyl; andwherein R_(j) is —D or —(O)CR_(d), wherein D and R_(d) are as definedabove.
 8. The method of claim 7, wherein the compound of structure IIIis a nitrosated yohimbine, a nitrosylated yohimbine, a nitrosated andnitrosylated yohimbine, a nitrosated apoyohimbine, a nitrosylatedapoyohimbine, a nitrosated and nitrosylated apoyohimbine, a nitrosatedcorynanthine, a nitrosylated corynanthine, a nitrosated and nitrosylatedcorynanthine, a nitrosated β-yohimbine, a nitrosylated β-yohimbine, anitrosated and nitrosylated β-yohimbine, a nitrosated yohimbol, anitrosylated yohimbol, a nitrosated and nitrosylated yohimbol, anitrosated pseudoyohimbine, a nitrosylated pseudoyohimbine, a nitrosatedand nitrosylated pseudoyohimbine, a nitrosated epi-3α-yohimbine, anitrosylated epi-3α-yohimbine, a nitrosated and nitrosylatedepi-3α-yohimbine, a nitrosated rauwolscine, a nitrosylated rauwolscine,a nitrosated and nitrosylated rauwolscine.
 9. The method of claim 7,wherein the compound of structure III is a nitrosated yohimbine, anitrosylated yohimbine, or a nitrosated and nitrosylated yohimbine. 10.The method of claim 7, wherein the compound that donates, transfers orreleases nitric oxide, elevates levels of endogenous endothelium-derivedrelaxing factor or stimulates endogenous nitric oxide synthesis is anS-nitrosothiol.
 11. The method of claim 10, wherein the S-nitrosothiolis S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione. 12.The method of claim 10, wherein the S-nitrosothiol is: (i)CH₃(C(R_(e))(R_(f)))_(x)SNO; (ii) HS(C(R_(e))(R_(f)))_(x)SNO; (iii)ONS(C(R_(e))(R_(f)))_(x)B; or (iv)H₂N—CH(CO₂H)—(CH₂)_(x)—C(O)NH—C(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein xequals 2 to 20; R_(e) and R_(f) are each independently a hydrogen, alower alkyl, a haloalkyl, an alkoxy, a carboxylic acid, a carboxylicester, a cycloalkyl, an aryl, a heteroaryl, an arylalkyl, an alkylamino,a dialkylamino, or —T—Q, or R_(e) and R_(f) taken together with thecarbon atoms to which they are attached are a carbonyl, a heterocyclicring, a cycloalkyl or a bridged cycloalkyl; T is a covalent bond,oxygen, sulfur or nitrogen, Q is NO or NO₂, and B is a fluoro, analkoxy, a cyano, a carboxamido, a cycloalkyl, an arylalkoxy, analkylsulfinyl, an arylthio, an alkylamino, a dialkylamino, a hydroxy, acarbamoyl, an N-alkylcarbamoyl, an N,N-dialkylcarbamoyl, an amino, ahydroxyl, a carboxyl, a hydrogen, a nitro or an aryl.
 13. The method ofclaim 7, wherein the compound that donates, transfers or releases nitricoxide, elevates levels of endogenous endothelium-derived relaxing factoror stimulates endogenous nitric oxide synthesis is: (i) a compoundcomprising at least one ON—O-, ON—N- or ON—C-group; (ii) aN-oxo-N-nitrosoamine comprising an R₁R₂—N(O—M⁺)—NO group, wherein M⁺ isa metal cation; and R₁ and R₂ are each independently a polypeptide, anamino acid, a sugar, an oligonucleotide, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic hydrocarbon, or a heterocyclic compound; (iii) a thionitratehaving the structure R₁₀—S—NO₂, wherein R₁₀ is a polypeptide, an aminoacid, a sugar, an oligonucleotide, or a straight or branched, saturatedor unsaturated, aliphatic or aromatic hydrocarbon; or (iv) a nitratehaving the structure R₁₀—O—NO₂, wherein R₁₀ is a polypeptide, an aminoacid, a sugar, an oligonucleotide, or a straight or branched, saturatedor unsaturated, aliphatic or aromatic hydrocarbon.
 14. The method ofclaim 13, wherein the compound comprising at least one ON—O-, ON—N- orON—C-group is an ON—N-polypeptide, an ON—C-polypeptide, an ON—N-aminoacid, an ON—C-amino acid, an ON—N-sugar, an ON—C-sugar, anON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched,saturated or unsaturated, aliphatic or aromatic ON—O-hydrocarbon, astraight or branched, substituted or unsubstituted, saturated orunsaturated, aliphatic or aromatic ON—N-hydrocarbon, a straight orbranched, substituted or unsubstituted, saturated or unsaturated,aliphatic or aromatic ON—C-hydrocarbon, an ON—N-heterocyclic compound oran ON—C-heterocyclic compound.
 15. The method of claim 7, wherein thecompound that donates, transfers or releases nitric oxide, elevateslevels of endogenous endothelium-derived relaxing factor or stimulatesendogenous nitric oxide synthesis is L-arginine.
 16. The method of claim7, wherein the compound that donates, transfers or releases nitricoxide, elevates levels of endogenous endothelium-derived relaxing factoror stimulates endogenous nitric oxide synthesis is a compound comprisingat least one O₂N—O-, O₂—N—N-, O₂N—S- or O₂N—C-group.
 17. The method ofclaim 16, wherein the compound comprising at least one O₂N—O-, O₂N—N-,O₂N—S- or O₂N—C-group is an O₂N—O-polypeptide, an O₂N—N-polypeptide, anO₂N—S-polypeptide, an O₂N—C-polypeptide, an O₂N—O-amino acid, anO₂N—N-amino acid, an O₂N—S-amino acid, an O₂N—C-amino acid, anO₂N—O-sugar, an O₂N—N-sugar, an O₂N—S-sugar, an O₂N-sugar, anO₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, anO₂N—S-oligonucleotide, an O₂N—C-oligonucleotide, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic O₂N—O-hydrocarbon, a straight or branched, saturated orunsaturated, substituted or unsubstituted, aliphatic or aromaticO₂N—N-hydrocarbon, a straight or branched, saturated or unsaturated,substituted or unsubstituted, aliphatic or aromatic O₂N—S-hydrocarbon, astraight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic O₂N—C-hydrocarbon, anO₂N—O-heterocyclic compound, an O₂N—N-heterocyclic compound, anO₂N—S-heterocyclic compound or an O₂N—C-heterocyclic compound.
 18. Themethod of claim 4, wherein the at least one compound of structure IIIand the at least one the compound that donates, transfers or releasesnitric oxide, elevates levels of endogenous endothelium-derived relaxingfactor or stimulates endogenous nitric oxide synthesis are together inthe form of a composition.
 19. The method of claim 7, wherein the atleast one compound that donates, transfers or releases nitric oxide ispresent in a one to ten fold molar excess with respect to the at leastone compound of structure III.
 20. The method of claim 7, wherein the atleast one compound of structure III and the at least one the compoundthat donates, transfers or releases nitric oxide, elevates levels ofendogenous endothelium-derived relaxing factor or stimulates endogenousnitric oxide synthesis are administered orally.
 21. The method of claim7, wherein the at least one compound of structure III and the at leastone the compound that donates, transfers or releases nitric oxide,elevates levels of endogenous endothelium-derived relaxing factor orstimulates endogenous nitric oxide synthesis are administeredparenterally.
 22. The method of claim 7, wherein the at least onecompound of structure III and the at least one the compound thatdonates, transfers or releases nitric oxide, elevates levels ofendogenous endothelium-derived relaxing factor or stimulates endogenousnitric oxide synthesis are administered topically.
 23. The method ofclaim 4, wherein the at least one compound of structure III isadministered orally in a solid dosage form or a liquid dosage form. 24.The method of claim 23, wherein the solid dosage form is a capsule, atablet, an effervescent tablet, a chewable tablet, a pill, a powder, asachet, a granule or a gel.
 25. The method of claim 23, wherein theliquid dosage form is an emulsion, a solution, a suspension, a syrup, oran elixir.
 26. The method of claim 7, wherein the least one compound ofstructure III and the at least one compound that donates, transfers orreleases nitric oxide, elevates levels of endogenous endothelium-derivedrelaxing factor or stimulates endogenous nitric oxide synthesis areadministered orally in a solid dosage form or a liquid dosage form. 27.The method of claim 26, wherein the solid dosage form is a capsule, atablet, an effervescent tablet, a chewable tablet, a pill, a powder, asachet, a granule or a gel.
 28. The method of claim 26, wherein theliquid dosage form is an emulsion, a solution, a suspension, a syrup, oran elixir.
 29. The method of claim 7, further comprising administering apharmaceutically acceptable carrier.
 30. The method of claim 7, whereinthe at least one compound of structure III and the at least one thecompound that donates, transfers or releases nitric oxide, elevateslevels of endogenous endothelium-derived relaxing factor or stimulatesendogenous nitric oxide synthesis are administered separately.